JP4446145B2 - Benzamidine derivatives - Google Patents

Abstract

A benzamidine derivative of the following formula, analogs thereof and pharmaceutically acceptable salts thereof have an effect of inhibiting the blood coagulation based on their excellent effect of inhibiting activated blood-coagulation factor X. Thus, a blood-coagulation inhibitor or an agent for preventing or treating thrombosis or embolism, containing one of those compounds as the active ingredient, is provided. <CHEM>

Description

［式中、Ｘは、水素原子、カルボキシル基、炭素数２〜４のアルコキシカルボニル基、置換基を有してもよい炭素数１〜３のアルキル基または置換基を有してもよいベンジル基のいずれかを表し、ここで、置換基を有する場合の置換基はカルボキシル基または炭素数２〜８のアルコキシカルボニル基のいずれかを表し、
Ｖは置換基を有してもよいベンゾイル基またはピペリジンカルボニル基のいずれかを表し、ここで、置換基を有する場合の置換基は炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数６〜１０のアリール基、炭素数４〜５のヘテロアリール基、カルバモイル基、または炭素数２〜７のモノもしくはジアルキルカルバモイル基のいずれかを表す。］
発明を実施するための最良の形態
本明細書におけるアルキル基、アルコキシカルボニル基、イミノアルキルピペリジルオキシ基等の成分としてのアルキル基は分岐、環を含んでいてもよい。アルキル基の例としてはメチル基、エチル基、プロピル基、イソプロピル基、シクロプロピル基などの炭素数１〜６、好ましくは１〜５のアルキル基が挙げられる。アルコキシカルボニル基の例としてはメトキシカルボニル基、エトキシカルボニル基、プロピルオキシカルボニル基、ベンジルオキシカルボニル基等の炭素数２〜１０、好ましくは２〜８のアルコキシカルボニル基が挙げられ、イミノアルキルピペリジルオキシ基の例としては１−アセトイミドイル−４−ピペリジルオキシ基等の炭素数７〜１０のものが挙げられる。
本明細書におけるアリール基はフェニル基、１−ナフチル基、２−ナフチル基等が挙げられ、ヘテロアリール基は窒素原子、酸素原子及び硫黄原子から選ばれる１〜２個の複素原子を有する芳香族複素環基が好ましく、例えばピリジル基、ピリミジル基、ピリダジニル基、ピラジニル基等が挙げられる。
本明細書におけるジアルキルカルバモイル基において、２つのアルキル基は結合して環を構成しても良い。また、このときメチレン基が酸素原子、アミノ基、硫黄原子で置換されてもよい。たとえば１−ピロリジンカルボニル基、１−ピペリジンカルボニル基、１−ピペラジンカルボニル基、１−モルホリンカルボニル基等があげられる。
上記一般式（１）において、Ｘで表される基としては、水素原子、カルボキシメチル基、カルボキシエチル基が好ましい。
Ｖで表される基としては、Ｖが置換基を有してもよいベンゾイル基またはピペリジンカルボニル基のいずれかを表し、ここで、置換基を有する場合の置換基が炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数６〜１０のアリール基、炭素数４〜５のヘテロアリール基、カルバモイル基、または炭素数２〜７のモノもしくはジアルキルカルバモイル基であるのが好ましい。このうち、Ｖで表される基としては、１−アセトイミドイル−４−ピペリジルオキシベンゾイル基、１−（４−ピリジル）−ピペリジン−４−カルボニル基、４−（１−ピロリジンカルボニル）ベンゾイル基が好ましい。
また、以下に示される式（２−１）〜（２−６）の化合物またはその医薬的に許容しうる塩が好ましい。

本発明のベンズアミジン誘導体（１）は次に示した方法を用いることにより製造することができる。例えば、一般式（１−１）は次のようにして製造する。
すなわち、窒素上を例えばベンジルオキシカルボニル基あるいはｔ−ブトキシカルボニル基で保護したアミノアルキルハライド（３）に、溶媒として例えばジメチルホルムアミド等を用い、例えば炭酸カリウム等の塩基存在下３−ヒドロキシ−４−ヨードベンゾニトリル（４）を作用させることによりヨードベンゾニトリル誘導体（５）を得ることができる。そして得られたヨードベンゾニトリル誘導体（５）を、溶媒として例えばジメチルホルムアミド等を用い、例えばＨｅｃｋ反応等により、リン酸ジエステル誘導体（６）へ導くことができる。得られたリン酸ジエステル誘導体（６）の窒素上の保護基は、例えば４規定塩化水素のジオキサン溶液等酸性溶液中で脱保護することによりアミン（７）を得ることができる。

続いて、溶媒として例えばジメチルホルムアミド等を用い、アミン（７）に、例えばトリエチルアミン等の塩基存在下、縮合剤を作用させることにより、カルボン酸との縮合を行い、アミド（８）を得ることができる。得られたアミド（８）に対し、例えば塩化水素等のハロゲン化水素を含有する、例えばエタノール等のアルコールを作用させ、続いて炭酸アンモニウム等のアンモニウム塩を反応させることによりシアノ基をアミジノ基へと変換し、アミジン誘導体（９）を得ることができる。アミジン誘導体（９）に対し、溶媒として例えばメタノール等のアルコールを用い、例えばバラジウムカーボン等の触媒存在下、水素雰囲気下で反応させ、続いて、例えば濃塩酸等の酸性水溶液により加水分解することにより、ベンズアミジン誘導体（１−１）を製造することができる。

このようにして製造される一般式（１）〜式（２−６）で示される化合物およびその塩は、公知の分離精製手段、例えば抽出、濃縮、減圧濃縮、溶媒抽出、晶析、再結晶、転溶、各種クロマトグラフィーなどにより単離精製することができる。
本発明の一般式（１）で示されるベンズアミジン誘導体は、不斉炭素を有する場合があるため光学活性体も考えられるが、本発明で示している化合物はこの光学活性体の混合物や単離されたものも含まれる。
本発明化合物におけるアミジノ基は、生体内でアミジノ基に交換される適当な置換により置換されていてもよい。例えば、一般式（１）において、ベンゼン環に結合しているアミジノ基の二重結合を有する窒素原子に結合している水素原子が、ヒドロキシル基、エトキシ基のようなアルコキシル基、アミノ基、カルボキシル基、エトキシカルボニル基のようなアルコキシカルボニル基、エチルスルホニル基のようなアルキルスルホニル基、カルバモイル基、ジエトキシカルバモイル基のような１または２の水素がアルキル基で置換しているカルバモイル基、ホルミル基、アセチル基のようなアシル基、アセトキシ基のようなアルキルカルボキシル基で置換されているものが挙げられる。このような基で置換されている本発明の化合物としては、式（２−５）及び（２−６）で示される化合物が挙げられる。
本発明の一般式（１）〜式（２−６）で示されるベンズアミジン誘導体の塩は、医薬的に許容しうるものであれば良く、例えば塩酸、臭化水素酸、硫酸、硝酸、リン酸等の鉱酸、ギ酸、酢酸、トリフルオロ酢酸、乳酸、サリチル酸、マンデル酸、クエン酸、シュウ酸、マレイン酸、フマル酸、酒石酸、タンニン酸、リンゴ酸、トシル酸、メタンスルホン酸、ベンゼンスルホン酸などの有機酸との酸付加塩を挙げることができる。
一般式（１）〜式（２−６）で示される化合物またはその塩は、そのままあるいは各種の医薬組成物として投与される。このような医薬組成物の剤形としては、例えば錠剤、散剤、丸剤、顆粒剤、カプセル剤、坐剤、溶液剤、糖衣剤、またはデボー剤にしてよく、普通の製剤助剤を用いて常法に従って製造する事ができる。例えば錠剤は、本発明の有効成分であるベンズアミジン誘導体を既知の補助物質、例えば乳糖、炭酸カルシウムまたは燐酸カルシウム等の不活性希釈剤、アラビアゴム、コーンスターチまたはゼラチン等の結合剤、アルギン酸、コーンスターチまたは前ゼラチン化デンプン等の膨化剤、ショ糖、乳糖またはサッカリン等の甘味剤、ペパーミントまたはチェリー等の香味剤、ステアリン酸マグネシウム、タルクまたはカルボキシメチルセルロース等の滑湿剤と混合することによって得られる。
一般式（１）〜式（２−６）で示されるベンズアミジン誘導体を抗凝固剤として使用する場合の投与経路は、経口、非経口のいずれであってもよく、投与量は患者の年齢、体重、状態、および投与法によって異なるが、成人への一日当りの投与量としては、通常、経口投与の場合で０．０１〜１０００ｍｇ、好ましくは０．１〜５０ｍｇであり、非経口投与の場合で１μｇ〜１００ｍｇ、好ましくは０．０１〜１０ｍｇである。
一般式（１）〜式（２−６）で示される化合物またはその塩を有効成分とする抗血液凝固剤又は血栓若しくは塞栓によって引き起こされる疾病の予防・治療剤は、例えば脳梗塞、脳卒中、脳血栓、脳塞栓、一過性脳虚血発作（ＴＩＡ）、くも膜下出血（血管れん縮）等の脳血管障害における疾病、急性及び慢性心筋梗塞、不安定狭心症、冠動脈血栓等の虚血性心疾患における疾病、肺梗塞、肺塞栓等の肺血管障害における疾病、末梢動脈閉塞症、深部静脈血栓症、汎発性血管内凝固症候群、さらに人工血管術及び人工弁置換後の血栓形成、冠動脈バイパス術後における再閉塞及び再狭窄、経皮的経管式冠動脈形成術（ＰＴＣＡ）または経皮的経管式冠動脈再開通療法（ＰＴＣＲ）等の血行再建後の再閉塞及び再狭窄、体外循環時の血栓形成などの予防・治療剤として利用できる。
以下の実施例により本発明を詳細に説明する。これらは本発明の好ましい実施態様であるが、本発明はこれらの実施例に限定されるものではない。
実施例１ ［２−（４−アミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸 二トリフルオロ酢酸塩
工程１ １−（４−ピリジル）−４−ピペリジンカルボン酸エチルの合成
４−クロロピリジン塩酸塩４．０ｇ（２６．６ｍｍｏｌ）、ピペリジン−４−カルボン酸エチル４．２ｇ（２６．６ｍｍｏｌ）、トリエチルアミン７．４ｍｌ（５３．２ｍｍｏｌ）をキシレン１００ｍｌ中１３０℃で２４時間撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２．９５ｇ（１２．６ｍｍｏｌ） 収率 ４７％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．２５（３Ｈ，ｔ），１．７１−１．８５（２Ｈ，ｍ），２．００（２Ｈ，ｄ），２．５０−２．６０（１Ｈ，ｍ），２．９０（２Ｈ，ｔ），３．８１（２Ｈ，ｄ），４．２０（２Ｈ，ｑ），６．６６（２Ｈ，ｄ），８．２６（２Ｈ，ｄ）
工程２ １−（４−ピリジル）−４−ピペリジンカルボン酸 塩酸塩の合成
１−（４−ピリジル）−４−ピペリジンカルボン酸エチル２．９５ｇ（１２．６ｍｍｏｌ）をジオキサン１００ｍｌ中撹拌し、１規定塩酸５０ｍｌを加え、９５℃で２０時間撹拌した。溶媒を留去して表題化合物の粗製物を得た。
収量 ３．２１ｇ（１１．５ｍｍｏｌ） 収率 ９１％
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．５４（２Ｈ，ｔ），１．９０（２Ｈ，ｔ），２．６０−２．７０（１Ｈ，ｍ），３．３０（２Ｈ，ｔ），４．１０（２Ｈ，ｄ），７．１９（２Ｈ，ｄ），８．２０（２Ｈ，ｄ）
工程３ ３−ヒドロキシ−４−ヨード安息香酸の合成
３−ヒドロキシ安息香酸３０．０ｇ（２１７ｍｍｏｌ）を酢酸２００ｍｌに溶解し、一塩化ヨウ素５３．０ｇ（３２６ｍｍｏｌ）を室温で加えた。４５℃で１５時間撹拌後、溶媒を減圧留去して得た残渣を１％チオ硫酸ナトリウム水溶液５００ｍｌで２回、水５００ｍｌで２回洗浄し、８０℃で減圧乾固させることで、表題化合物を得た。
収量 １７．２ｇ（６５．２ｍｍｏｌ） 収率 ３０％
ＭＳ（ＦＡＢ，ｍ／ｚ） ２６５（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ ７．１３（１Ｈ，ｄｄ），７．４３（１Ｈ，ｄ），７．８０（１Ｈ，ｄ）
工程４ ３−ヒドロキシ−４−ヨードベンゾニトリルの合成
３−ヒドロキシ−４−ヨード安息香酸２２．３ｇ（８９．７ｍｍｏｌ）をテトラヒドロフラン３００ｍｌに溶解したものにクロロギ酸エチル１９．７ｍｌ（２０６ｍｍｏｌ）、トリエチルアミン２８．７ｍｌ（２０６ｍｍｏｌ）を０℃で加えた。１５分撹拌後、生成したトリエチルアミン塩酸塩を濾別し、アンモニアをバブリングして得られたテトラヒドロフラン溶液３００ｍｌに、濾液を０℃で加えた。室温で１０時間撹拌後、溶媒を減圧留去して得られた残留物をジオキサン４５０ｍｌに溶解し無水トリフルオロメタンスルホン酸１７．４ｍｌ（１１７ｍｍｏｌ）、ピリジン２１．８ｍｌ（２６９ｍｍｏｌ）を０℃で加えた。室温で１８時間撹拌後、溶媒を減圧留去して得られた残留物をクロロホルムを抽出溶媒とし常法に従って処理し油状残渣を得た。得られた残留物をテトラヒドロフラン：メタノール（１：１）１８０ｍｌに溶解したものに１規定水酸化ナトリウム水溶液９０ｍｌ（９０．０ｍｍｏｌ）を室温で加えた。そのまま４時間撹拌後、溶媒を減圧留去し、得られた残留物をジクロロメタンで洗浄した。続いて、１規定塩化水素で酸性とし酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ９．２９ｇ（３７．９ｍｍｏｌ） 収率 ４２％
ＭＳ（ＦＡＢ，ｍ／ｚ） ２４６（ＭＨ＋）
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ ５．６３（１Ｈ，ｂｒ），６．９６（１Ｈ，ｄｄ），７．２３（１Ｈ，ｄ），７．７９（１Ｈ，ｄ）
工程５ ｔ−ブチル（２−ブロモエチル）カルバマートの合成
２−ブロモエチルアミン 臭化水素酸塩９．２２ｇ（４５ｍｍｏｌ）をジクロロメタン１００ｍｌに溶解し、ジ−ｔ−ブチルジカルボネート７．６４ｇ（３５ｍｍｏｌ）、トリエチルアミン１０．０ｇ（９９ｍｍｏｌ）、４−（ジメチルアミノ）ピリジン１００ｍｇ（０．８２ｍｍｏｌ）を加え一晩撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ５．９９ｇ（２６．７ｍｍｏｌ） 収率 ７６％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．４５（９Ｈ，ｓ），３．４６（２Ｈ，ｄｔ），３．５１（２Ｈ，ｔ），４．９５（１Ｈ，ｂｒ）
工程６ ３−［２−（ｔ−ブトキシカルボニルアミノ）エトキシ）−４−ヨードベンゾニトリルの合成
ｔ−ブチル（２−ブロモエチル）カルバマート１８．５ｇ（８２．６ｍｍｏｌ）をＤＭＦ２００ｍｌに溶解させ、３−ヒドロキシ−４−ヨードベンゾニトリル１０．１ｇ（４１．３ｍｍｏｌ）、炭酸カリウム５．７ｇ（４１．３ｍｍｏｌ）を加え７５℃で３時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 １１．０ｇ（２８．４ｍｍｏｌ） 収率 ６９％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．４６（９Ｈ，ｓ），３．６２（２Ｈ，ｄｔ），４．１２（２Ｈ，ｔ），７．０２（２Ｈ，ｄ），７．８８（２Ｈ，ｄ）．
工程７ ２−（２−（ｔ−ブトキシカルボニルアミノ）エトキシ）−４−シアノ−安息香酸メチルエステルの合成
３−（２−（ｔ−ブトキシカルボニルアミノ）エトキシ）−４−ヨードベンゾニトリル５ｇ（１２．８８ｍｍｏｌ）をＮ、Ｎ−ジメチルホルムアミド（脱水）６０ｍｌに溶解し、トリエチルアミン３．６ｍｌ（２５．８ｍｍｏｌ）、メタノール１０ｍｌ（２５．８ｍｍｏｌ）、酢酸パラジウム１４５ｍｇ（０．６４４ｍｍｏｌ）を加え、一酸化炭素存在下９０℃で６時間攪拌した。溶媒を留去し酢酸エチルを抽出溶媒として常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ４．１１ｇ（１２．８２ｍｍｏｌ） 収率 ９９．５％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．４４（９Ｈ，ｓ），３．６１（２Ｈ，ｑ），３．９４（３Ｈ，ｓ），４．１２（２Ｈ，ｍ），５．３８（１Ｈ，ｂｒ），７．２１（１Ｈ，ｓ），７．３８（１Ｈ，ｍ），７．８７（１Ｈ，ｄ）．
工程８ ３−（２−（ｔ−ブトキシカルボニルアミノ）エトキシ）−４−ヒドロキシメチルベンゾニトリルの合成
２−（２−（ｔ−ブトキシカルボニルアミノ）エトキシ）−４−シアノ−安息香酸メチルエステル４．１５ｇ（１２．９５ｍｍｏｌ）をテトラヒドロフラン（脱水）６０ｍｌに溶解し、氷冷下２Ｍリチウムボロハイドライド８．６ｍｌ（１７．２ｍｍｏｌ）加え、室温で一晩攪拌した。溶媒を留去し酢酸エチルを抽出溶媒として常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２．３８ｇ（８．１２ｍｍｏｌ） 収率 ６３％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．４１（９Ｈ，ｓ），３．００（１Ｈ，ｂｒ），３．６０（２Ｈ，ｂｒ），４．１０（２Ｈ，ｔ），４．７０（２Ｈ，ｄ），４．９５（１Ｈ，ｂｒ），７．０７（１Ｈ，ｓ），７．３０（１Ｈ，ｄ），７．４１（１Ｈ，ｄ）．
工程９ ３−（２−（ｔ−ブトキシカルボニルアミノ）エトキシ）−４−ホルミルベンゾニトリルの合成
３−（２−（ｔ−ブトキシカルボニルアミノ）エトキシ）−４−ヒドロキシメチルベンゾニトリル０．３ｇ（１．０３ｍｍｏｌ）をジクロロメタン（脱水）３ｍｌに溶解し、活性化二酸化マンガン０．３６ｇ（４．１ｍｍｏｌ）をアルゴン存在下加え室温で一晩攪拌した。反応液をセライト濾過し、表題化合物を得た。
収量 ２７９ｍｇ（０．９６２ｍｍｏｌ） 収率 ９３％
ＭＳ（ＥＳＩ，ｍ／ｚ） ２９１（ＭＨ−）
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．５３（９Ｈ，ｓ），３．６２（２Ｈ，ｑ），４．２０（２Ｈ，ｔ），４．９５（１Ｈ，ｂｒ），７．３５（２Ｈ，ｍ），７．９３（１Ｈ，ｄ），１０．５０（１Ｈ，ｓ）．
工程１０ ［２−［（２−（２−ｔ−ブトキシカルボニルアミノ）エトキシ）−４−シアノ−フェニル］ビニル］リン酸ジエチルエステルの合成
テトラエチルメチレンジホスホネート０．５４ｍｌ（２．１８ｍｍｏｌ）をテトラヒドロフラン（脱水）１０ｍｌに溶解し、−７８℃にてアルゴン存在下１．５４Ｍｎ−ブチルリチウムヘキサン溶液１．５ｍｌ（１．０ｍｍｏｌ）を加え２０分攪拌したのち、３−（２−（ｔ−ブトキシカルボニルアミノ）エトキシ）−４−ホルミルベンゾニトリル５２７ｍｇ（１．８２ｍｍｏｌ）を加え−７８℃で４５分攪拌し室温にあげ３時間攪拌した。溶媒を留去しジクロロメタンを抽出溶媒として常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ０．４５ｇ（１．０６ｍｍｏｌ） 収率 ５８％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．１７−１．４２（６Ｈ，ｍ），１．４７（９Ｈ，ｓ），３．６０（２Ｈ，ｂｒ），３．９６−４．２３（６Ｈ，ｍ），５．００（１Ｈ，ｂｒ），６．４０（２Ｈ，ｍ），７．１５（１Ｈ，ｓ），７．２７（１Ｈ，ｄ），７．５８（１Ｈ，ｄ）．
工程１１ ［２−（４−アミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステル 二トリフルオロ酢酸塩合成
［２−（４−アミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）ビニル］リン酸モノエチルエステル 二トリフルオロ酢酸塩合成
［２−［（２−（２−ｔ−ブトキシカルボニルアミノ）エトキシ）−４−シアノ−フェニル］ビニル］リン酸ジエチルエステル０．４５ｇ（１．０６ｍｍｏｌ）をジオキサン５ｍｌ、４規定塩化水素ジオキサン溶液５ｍｌに溶解させ、室温で３時間撹拌した。溶媒を留去して得られた粗製物をＮ、Ｎ−ジメチルホルムアミド（脱水）１０ｍｌに溶解し、１−（４−ピリジル）−４−ピペリジンカルボン酸塩酸塩０．２９ｇ（１．２ｍｍｏｌ）、２−クロロ−１、３−ジメチルイミダゾニウムクロライド０．５ｇ（２．８ｍｍｏｌ）、トリエチルアミン１．８ｍｌ（１２．８ｍｍｏｌ）を加え、一晩撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。得られた粗製物を４規定塩化水素ジオキサン溶液５ｍｌ、エタノール０．５ｍｌに溶解し、室温で３日間攪拌した。溶媒を留去して得られた残留物をエタノール５ｍｌに溶解し、炭酸アンモニウム０．１９ｇ（３．３５ｍｍｏｌ）を加え、室温で一晩攪拌した。溶媒を留去して得られた粗製物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的フラクションを凍結乾燥することにより表題化合物を得た。
［２−（４−アミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステル 二トリフルオロ酢酸塩
収量 １５５ｍｇ（０．２０４ｍｍｏｌ） 収率 ３１％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５３０（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．２６（６Ｈ，ｔ），１．５０−１．９２（４Ｈ，ｍ），２．５８（２Ｈ，ｂｒ），３．２２（２Ｈ，ｔ），３．５０（２Ｈ，ｂｒ），４．０３（４Ｈ，ｍ），４．２０（３Ｈ，ｂｒ），６．７７（２Ｈ，ｍ），７．１９（２Ｈ，ｄ），７．４０−７．７４（３Ｈ，ｍ），７．９６（１Ｈ，ｄ），８．２１（２Ｈ，ｄ），９．３３（２Ｈ，ｂｒ），９．３６（２Ｈ，ｂｒ）．
［２−（４−アミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）ビニル］リン酸モノエチルエステル 二トリフルオロ酢酸塩合成
収量 ６３．４ｍｇ（０．０８７ｍｍｏｌ） 収率 １３％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５０２（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．２３（３Ｈ，ｔ），１．５０−１．９５（４Ｈ，ｍ），２．５８（２Ｈ，ｂｒ），３．２２（２Ｈ，ｔ），３．５０（２Ｈ，ｂｒ），３．９５（２Ｈ，ｍ），４．２２（３Ｈ，ｂｒ），６．７１（２Ｈ，ｍ），７．１８（２Ｈ，ｄ），７．３８−７．６６（３Ｈ，ｍ），７．９２（１Ｈ，ｄ），８．２０（２Ｈ，ｄ），９．２１（２Ｈ，ｂｒ），９．３４（２Ｈ，ｂｒ）．
工程１２ ［２−（４−アミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 二トリフルオロ酢酸塩の合成
［２−（４−アミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）ビニル］リン酸モノエチルエステル 二トリフルオロ酢酸塩６３．４ｍｇ（０．０８７ｍｍｏｌ）ｇをエタノール２ｍｌに溶解し、アルゴン下１０％パラジウム−炭素（５０％含水）１０ｍｇ加え水素存在下室温で一晩攪拌した。水２ｍｌ加え、溶媒を留去して得られた粗製物を実施例 １工程 １１と同様の操作により表題化合物を得た。
収量 ４３．１ｍｇ（０．０５９ｍｍｏｌ） 収率 ６８％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５０４（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．２０（３Ｈ，ｔ），１．５８（２Ｈ，ｂｒ），１．８０−１．９６（４Ｈ，ｍ），２．６２（２Ｈ，ｂｒ），２．８０（２Ｈ，ｂｒ），３．２１（２Ｈ，ｔ），３．４９（２Ｈ，ｑ），３．８８−３．９８（２Ｈ，ｍ），４．１２（２Ｈ，ｔ），４．２０（１Ｈ，ｂｒ），７．１８（２Ｈ，ｄ），７．３７−７．４２（３Ｈ，ｍ），８．２１（２Ｈ，ｄ），８．２８（１Ｈ，ｂｒ），９．１８（２Ｈ，ｂｒ），９．２５（２Ｈ，ｂｒ）．
工程１３ ［２−（４−アミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸 二トリフルオロ酢酸塩
［２−（４−アミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 二トリフルオロ酢酸塩２７．５ｍｇ（３７．５９ｍｍｏｌ）ｇを濃塩酸２ｍｌに溶解し、８０℃で１１時間攪拌した。溶媒を留去して得られた粗製物を実施例１工程１１と同様の操作により表題化合物を得た。
収量 ９ｍｇ（１２．７９ｍｍｏｌ） 収率 ３４％
ＭＳ（ＥＳＩ，ｍ／ｚ） （ＭＨ＋）４７６
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．５０−２．２０（６Ｈ，ｍ），２．６９（２Ｈ，ｂｒ），２．８３（２Ｈ，ｂｒ），３．１４−３．３６（２Ｈ，ｍ），３．４９（２Ｈ，ｂｒ），４．０７−４．２６（３Ｈ，ｍ），７．１４−７．２４（３Ｈ，ｍ），７．３２−７．４４（２Ｈ，ｍ），８．２１（２Ｈ，ｄ），８．３４（１Ｈ，ｂｒ），９．２３（３Ｈ，ｂｒ）．
実施例２ ［２−（４−アミジノ−２−［２−［４−（１−（１−アセトイミドイル）−４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸 二トリフルオロ酢酸塩
工程１ ［２−［（２−（２−ｔ−ブトキシカルボニルアミノ）エトキシ）−４−シアノ−フェニル］ビニル］リン酸ジエチルエステルの合成
３−（２−（ｔ−ブトキシカルボニルアミノ）エトキシ）−４−ヨードベンゾニトリル１０ｇ（２５．７６ｍｍｏｌ）をＮ、Ｎ−ジメチルホルムアミド（脱水）１００ｍｌに溶解し、ジエチルビニルホスホネート４．７５ｍｌ（３０．９１ｍｍｏｌ）、酢酸パラジウム５８ｍｇ（０．２５８ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン１６０ｍｇ（０．５１５ｍｍｏｌ）を加え、１００℃で一晩攪拌した。溶媒を留去し酢酸エチルを抽出溶媒として常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ９．４６ｇ（２２．３ｍｍｏｌ） 収率 ８７％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．３８（６Ｈ，ｔ），２．１５（２Ｈ，ｂｒ），３．６０（２Ｈ，ｂｒ），４．１１（４Ｈ，ｍ），５．１８（１Ｈ，ｂｒ），６．４０（１Ｈ，ｔ），７．１３（１Ｈ，ｓ），７．２９（１Ｈ，ｍ），７．５８（１Ｈ，ｄ），７．７２−７．８６（１Ｈ，ｍ）．
工程２ ［２−（４−アミジノ−２−［２−［４−（４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステル 二トリフルオロ酢酸塩の合成
［２−［（２−（２−ｔ−ブトキシカルボニルアミノ）エトキシ）−４−シアノ−フェニル］ビニル］リン酸ジエチルエステル１．５ｇ（３．５３ｍｍｏｌ）をジオキサン１５ｍｌ、４規定塩化水素ジオキサン溶液１５ｍｌに溶解させ、室温で２時間撹拌した。溶媒を留去して得られた粗製物をＮ、Ｎ−ジメチルホルムアミド（脱水）１０ｍｌに溶解し、４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸１．２５ｇ（３．８８ｍｍｏｌ）、２−クロロ−１、３−ジメチルイミダゾニウムクロライド０．７８ｇ（４．５９ｍｍｏｌ）、トリエチルアミン３ｍｌ（２１．２ｍｍｏｌ）を加え、４時間撹拌し、溶媒を留去した。得られた粗製物を４規定塩化水素ジオキサン溶液５０ｍｌに溶解し、エタノール５ｍｌ加え、室温で一晩攪拌した。溶媒を留去して得られた残留物をエタノール１０ｍｌに溶解し、炭酸アンモニウム１ｇ（１７．６５ｍｍｏｌ）を加え、室温で一晩攪拌した。溶媒を留去し得られた粗製物をジオキサン３０ｍｌ、４規定塩化水素ジオキサン溶液３０ｍｌに溶解させ、室温で２時間撹拌した。溶媒を留去して得られた粗製物を実施例１工程１１と同様の操作により表題化合物を得た。
収量 １．４５ｇ（１．８８ｍｍｏｌ） 収率 ５３％
工程３ ［２−（４−アミジノ−２−［２−［４−（１−（１−アセトイミドイル）−４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸ジエチルエステル 二トリフルオロ酢酸塩の合成
行程２で得られた［２−（４−アミジノ−２−［２−［４−（４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステル 二トリフルオロ酢酸塩１．４５ｇ（１．８８ｍｍｏｌ）をエタノール５０ｍｌに溶解し、エチルアセトイミデート塩酸塩０．６９５ｇ（５．６５ｍｍｏｌ）、トリエチルアミン１．３１ｍｌ（９．３８ｍｍｏｌ）加え、一晩撹拌した。溶媒を留去して得られた粗製物をエタノール５０ｍｌに溶解し、１０％パラジウム−炭素１５０ｍｇを加え、水素存在下一晩撹拌した。セライト濾過し、溶媒を留去し、得られた粗精製物を実施例１の行程１１と同様の操作を行い表題化合物を得た。
収量 ９８ｍｇ（０．１２ｍｍｏｌ） 収率 ６％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５８８（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．１７（６Ｈ，ｔ），１．８０（２Ｈ，ｂｒ），１．９５−２．２０（４Ｈ，ｍ），２．３０（３Ｈ，ｓ），２．８５（２Ｈ，ｂｒ），３．４０−３．８０（６Ｈ，ｍ），３．９０（４Ｈ，ｑ），４．２５（２Ｈ，ｂｒ），４．８０（１Ｈ，ｂｒ），７．０６（２Ｈ，ｄ），７．４２（３Ｈ，ｍ），７．８６（２Ｈ，ｄ），８．６０（２Ｈ，ｂｒ），９．１１（３Ｈ，ｂｒ），９．２６（２Ｈ，ｂｒ）．
工程４ ［２−（４−アミジノ−２−［２−［４−（４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 二トリフルオロ酢酸塩の合成
［２−（４−アミジノ−２−［２−［４−（４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸 二トリフルオロ酢酸塩の合成
行程２と同様の操作から得られた［２−（４−シアノ−２−［２−［４−（１−（１−ｔ−ブトキシカルボニル）−４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステル０．３ｇ（０．４７８ｍｍｏｌ）をエタノール３０ｍｌに溶解し、１０％パラジウム−炭素３０ｍｇを加え、水素存在下一晩撹拌した。セライト濾過し、溶媒を留去した粗精製物をジオキサン１０ｍｌ、４規定塩化水素ジオキサン溶液１０ｍｌに溶解させ、室温で１時間撹拌した。溶媒を留去し得られた粗製物を４規定塩化水素ジオキサン溶液３０ｍｌに溶解し、エタノール３ｍｌ加え、室温で一晩攪拌した。溶媒を留去して得られた残留物をエタノール１０ｍｌに溶解し、炭酸アンモニウム０．２ｇ（３．５ｍｍｏｌ）を加え、室温で一晩攪拌した。溶媒を留去し得られた粗製物を濃塩酸５ｍｌ溶解し、８０℃で４時間撹拌した。溶媒を留去し、実施例１の行程１１と同様の操作を行い表題化合物を得た。
［２−（４−アミジノ−２−［２−［４−（４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 二トリフルオロ酢酸塩
収量 ５３．２ｍｇ（０．０７ｍｍｏｌ） 収率 １５％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５１９（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．１６（３Ｈ，ｔ），１．７５−２．００（４Ｈ，ｍ），２．１０（２Ｈ，ｂｒ），２．８５（２Ｈ，ｂｒ），３．１０（２Ｈ，ｂｒ），３．２５（２Ｈ，ｂｒ），３．６０−４．００（４Ｈ，ｍ），４．２０（２Ｈ，ｂｒ），４．７５（１Ｈ，ｂｒ），７．０５（２Ｈ，ｄ），７．４１（３Ｈ，ｍ），７．８６（２Ｈ，ｄ），８．６０（２Ｈ，ｍ），９．１０（２Ｈ，ｂｒ），９．２５（２Ｈ，ｂｒ）．
［２−（４−アミジノ−２−［２−［４−（４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸
収量 ６．９６ｍｇ（０．００９６ｍｍｏｌ） 収率 ２％
ＭＳ（ＥＳＩ，ｍ／ｚ） ４９１（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．８０（４Ｈ，ｂｒ），２．１０（２Ｈ，ｂｒ），２．９５（２Ｈ，ｂｒ），３．００−３．７５（６Ｈ，ｍ），４．２０（２Ｈ，ｂｒ），４．７０（１Ｈ，ｂｒ），７．０５（２Ｈ，ｄ），７．４０（３Ｈ，ｍ），７．８８（２Ｈ，ｄ），８．５６（１Ｈ，ｂｒ），８．７４（１Ｈ，ｂｒ），９．０６（２Ｈ，ｂｒ），９．２２（２Ｈ，ｂｒ）．
工程５ ［２−（４−アミジノ−２−［２−［４−（１−（１−アセトイミドイル）−４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 二トリフルオロ酢酸塩の合成
行程４で得られた［２−（４−アミジノ−２−［２−［４−（４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 二トリフルオロ酢酸塩４６．９４ｍｇ（０．０６３ｍｍｏｌ）をエタノール５ｍｌに溶解し、エチルアセトイミデート塩酸塩７５ｍｇ（０．５７ｍｍｏｌ）、トリエチルアミン０．１５ｍｌ（０．９４５ｍｍｏｌ）加え、一晩撹拌した。溶媒を留去し、実施例１の行程１１と同様の操作を行い表題化合物を得た。
収量 ３４．２６ｍｇ（ｍｍｏｌ） 収率 ６９％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５６０（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．１６（３Ｈ，ｔ），１．７０−２．００（４Ｈ，ｍ），２．１０（２Ｈ，ｂｒ），２．３０（３Ｈ，ｓ），２．８５（２Ｈ，ｍ），３．５０（２Ｈ，ｍ），３．６０−３．８０（４Ｈ，ｍ），３．８８（２Ｈ，ｑ），４．２０（２Ｈ，ｂｒ），４．８０（１Ｈ，ｂｒ），７．０６（２Ｈ，ｄ），７．４１（３Ｈ，ｍ），７．８６（２Ｈ，ｄ），８．６０（１Ｈ，ｂｒ），８．６６（１Ｈ，ｂｒ），９．１３（３Ｈ，ｂｒ），９．２４（２Ｈ，ｂｒ）．
工程６ ［２−（４−アミジノ−２−［２−［４−（１−（１−アセトイミドイル）−４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸 二トリフルオロ酢酸塩
行程４で得られた［２−（４−アミジノ−２−［２−［４−（４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸 二トリフルオロ酢酸塩６．９６ｍｇ（０．００９６ｍｍｏｌ）をエタノール５ｍｌに溶解し、エチルアセトイミデート塩酸塩１４ｍｇ（０．０８６ｍｍｏｌ）、トリエチルアミン０．０３ｍｌ（０．１４４ｍｍｏｌ）加え、一晩撹拌した。溶媒を留去し、実施例１の行程１１と同様の操作を行い表題化合物を得た。
収量 ４．８７ｍｇ（０．００６４ｍｍｏｌ） 収率 ６７％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５３２（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．７０−１．９０（４Ｈ，ｍ），２．１０（２Ｈ，ｂｒ），２．３０（３Ｈ，ｓ），２．８５（２Ｈ，ｂｒ），２．６５（２Ｈ，ｂｒ），３．６０−３．８５（４Ｈ，ｍ），４．２０（２Ｈ，ｂｒ），４．８０（１Ｈ，ｂｒ），７．０６（２Ｈ，ｄ），７．４０（３Ｈ，ｍ），７．８７（２Ｈ，ｄ），８．６０（１Ｈ，ｂｒ），８．７２（１Ｈ，ｂｒ），９．０８（２Ｈ，ｂｒ），９．１６（１Ｈ，ｂｒ），９．２２（２Ｈ，ｂｒ）．
実施例３ ［２−（４−アミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸 一トリフルオロ酢酸塩
工程１ ［２−（４−シアノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステルの合成
［２−［（２−（２−ｔ−ブトキシカルボニルアミノ）エトキシ）−４−シアノ−フェニル］ビニル］リン酸ジエチルエステル化合物０．５７ｇ（１．３４ｍｍｏｌ）をジオキサン１０ｍｌ、４規定塩化水素ジオキサン溶液１０ｍｌに溶解させ、室温で１時間半撹拌した。溶媒を留去して得られた粗製物をＮ、Ｎ−ジメチルホルムアミド（脱水）２０ｍｌに溶解し、ピロリジルカルバモイル安息香酸０．３２ｇ（１．４７ｍｍｏｌ）、２−クロロ−１、３−ジメチルイミダゾニウムクロライド０．３２ｇ（１．７４ｍｍｏｌ）、トリエチルアミン１．２ｍｌ（８．０４ｍｍｏｌ）を加え、一晩撹拌し、溶媒を留去した。得られた粗製物を実施例１の行程１１と同様の操作を行い表題化合物を得た。
収量 ０．５２ｇ（０．９９ｍｍｏｌ） 収率 ７４％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５２６（ＭＨ＋）
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．３４（６Ｈ，ｔ），１．８０−２．０５（４Ｈ，ｍ），３．４０（２Ｈ，ｔ），３．６０（２Ｈ，ｔ），３．９５（２Ｈ，ｂｒ），４．１３（４Ｈ，ｑ），４．２５（２Ｈ，ｔ），６．４０（２Ｈ，ｍ），７．１７（１Ｈ，ｓ），７．５４（２Ｈ，ｄ），７．６３（１Ｈ，ｄ），７．８５（２Ｈ，ｄ），８．２０（１Ｈ，ｄ）．
行程２ ［２−（４−アミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸ジエチルエステル 一トリフルオロ酢酸塩の合成
行程１で得られた［２−（４−シアノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステル０．５ｇ（０．９５ｍｍｏｌ）を４規定塩化水素ジオキサン溶液１０ｍｌに溶解し、エタノール１ｍｌ加え、室温で一晩攪拌した。溶媒を留去して得られた残留物をエタノール５ｍｌに溶解し、炭酸アンモニウム０．３ｇ（４．７６ｍｍｏｌ）を加え、室温で一晩攪拌した。溶媒を留去し、得られた粗製物をエタノール５ｍｌに溶解し、１０％パラジウム−炭素０．１ｇを加え、室温で水素存在下一晩撹拌した。セライト濾過し、溶媒を留去し得られた粗精製物を実施例１の行程１１と同様の操作を行い表題化合物を得た。
収量 ３０６ｍｇ（０．４６ｍｍｏｌ） 収率 ４９％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５４５（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．１６（６Ｈ，ｔ），１．７５−２．１０（６Ｈ，ｍ），２．８３（２Ｈ，ｂｒ），３．３５（２Ｈ，ｔ），３．４５（２Ｈ，ｔ），３．７０−４．００（６Ｈ，ｍ），４．３０（２Ｈ，ｂｒ），７．４２（２Ｈ，ｍ），７．５８（３Ｈ，ｍ），７．９０（２Ｈ，ｄ），８．８６（１Ｈ，ｂｒ），９．０２（２Ｈ，ｂｒ），９．２５（２Ｈ，ｂｒ）．
行程３ ［２−（４−アミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 一トリフルオロ酢酸塩の合成
［２−（４−アミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸 一トリフルオロ酢酸塩の合成
行程２で得られた化合物［２−（４−アミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸ジエチルエステル 一トリフルオロ酢酸塩 ２６８ｍｇ（０．４１ｍｍｏｌ）を濃塩酸３ｍｌに溶解し、８０℃で８時間撹拌した。溶媒を留去し、実施例１の行程１１と同様の操作を行い表題化合物を得た。
［２−（４−アミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 一トリフルオロ酢酸塩
収量 １４．０７ｍｇ（０．０２２ｍｍｏｌ） 収率 ５％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５１７（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．１６（３Ｈ，ｔ），１．７８−２．００（６Ｈ，ｍ），２．８５（２Ｈ，ｂｒ），３．３４（２Ｈ，ｂｒ），３．４７（２Ｈ，ｂｒ），３．７２（２Ｈ，ｂｒ），３．９０（２Ｈ，ｍ），４．３０（２Ｈ，ｂｒ），７．４１（３Ｈ，ｍ），７．５８（２Ｈ，ｄ），７．９１（２Ｈ，ｄ），８．９０（１Ｈ，ｂｒ），９．０１（２Ｈ，ｂｒ），９．２２（２Ｈ，ｂｒ）．
［２−（４−アミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸 一トリフルオロ酢酸塩
収量 ７．８ｍｇ（０．０１３ｍｍｏｌ） 収率 ３％
ＭＳ（ＥＳＩ，ｍ／ｚ） ４８９（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．７５−１．９２（６Ｈ，ｍ），２．８５（２Ｈ，ｂｒ），３．３５（２Ｈ，ｂｒ），３．５０（２Ｈ，ｂｒ），３．７０（２Ｈ，ｂｒ），４．２５（２Ｈ，ｂｒ），７．４０（３Ｈ，ｍ），７．５９（２Ｈ，ｄ），７．９１（２Ｈ，ｄ），８．９４（１Ｈ，ｂｒ），９．００（２Ｈ，ｂｒ），９．２３（２Ｈ，ｂｒ）．
実施例４ （４Ｓ）−５−（５−アミジノ−２−（２−（ジエトキシリン酸）エチル）フェノキシ）−４−（（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ）ペンタン酸 二トリフルオロ酢酸塩
工程１ ベンジル（４Ｓ）−４−（（ｔ−ブトキシカルボニル）アミノ）−５−ヒドロキシペンタン酸の合成
ｔ−ブトキシカルボニル−Ｄ−グルタミン酸−γ−ベンジルエステル２５ｇ（７４．１ｍｍｏｌ）をテトラヒドロフラン３５０ｍｌに溶解したものにクロロギ酸エチル７．１ｍｌ（７４．１ｍｍｏｌ）、トリエチルアミン１０．３ｍｌ（７４．１ｍｍｏｌ）を０℃で加えた。２０分撹拌後、生成したトリエチルアミン塩酸塩を濾別し、氷５ｇ、水素化ホウ素ナトリウム２．８ｇ（７４．１ｍｍｏｌ）を０℃で加え、室温で１時間撹拌し、１規定塩化水素１００ｍｌ加え、１時間撹拌した。溶媒を留去して得られた残留物を酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １１．２５ｇ（３４．８ｍｍｏｌ） 収率 ４７％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．４３（９Ｈ，ｓ），２．５０（２Ｈ，ｂｒ），３．５０−３．７０（４Ｈ，ｍ），４．８０（１Ｈ，ｂｒ），５．１０（２Ｈ，ｓ），７．３５（５Ｈ，ｓ）．
工程２ ベンジル（４Ｓ）−４−（（ｔ−ブトキシカルボニル）アミノ）−５−（３−エテニルフェノキシ）ペンタン酸の合成
行程１で得られたベンジル（４Ｓ）−４−（（ｔ−ブトキシカルボニル）アミノ）−５−ヒドロキシペンタン酸１１．２５ｇ（３４．８ｍｍｏｌ）をジクロロメタン１２０ｍｌに溶解し、トリエチルアミン９．７ｍｌ（６９．６ｍｍｏｌ）を加え０℃で、メシルクロライド６．０ｍｌ（５２．２ｍｍｏｌ）加え室温で４時間撹拌した。溶媒を留去し、酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。得られた粗製物を、Ｎ、Ｎ−ジメチルホルムアミド（脱水）１００ｍｌに溶解し、リチウムクロライド７．４ｇ（１７４ｍｍｏｌ）を加え、５０℃で６時間撹拌した。溶媒を留去し、酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。得られた粗製物をＮ、Ｎ−ジメチルホルムアミド（脱水）１５０ｍｌに溶解し、３−ヒドロキシ−４−ヨードベンゾニトリル６．８ｇ（２７．７ｍｍｏｌ）、炭酸カリウム５．７３ｇ（４１．５ｍｍｏｌ）、よう化カリウム４．６ｇ（２７．７ｍｍｏｌ）を加え、９０℃で一晩撹拌した。溶媒を留去し、酢酸エチルを抽出溶媒として常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ６．６４ｇ（１３．５ｍｍｏｌ） 収率 ３９％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．４４（９Ｈ，ｓ），２．５０（２Ｈ，ｂｒ），３．６０（２Ｈ，ｂｒ），３．９３（２Ｈ，ｂｒ），４．９０（１Ｈ，ｂｒ），５．１０（２Ｈ，ｓ），６．９４−７．０４（２Ｈ，ｍ），７．３６（５Ｈ，ｓ），７．８８（１Ｈ，ｄ）．
工程３ ベンジル（４Ｓ）−４−（（ｔ−ブトキシカルボニル）アミノ）−５−（２−（（Ｅ）−２−（ジエトキシホスフォリル）エテニル）−５−エテニルフェノキシ）ペンタン酸の合成
行程２で得られたベンジル（４Ｓ）−４−（（ｔ−ブトキシカルボニル）アミノ）−５−（３−エテニルフェノキシ）ペンタン酸２．２ｇ（４．４７ｍｍｏｌ）をＮ、Ｎ−ジメチルホルムアミド（脱水）２０ｍｌに溶解し、ジエチルビニルホスフォネート０．８２ｍｌ（５．３６ｍｍｏｌ）、酢酸パラジウム１１ｍｇ（０．０５ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン３０ｍｇ（０．０９ｍｍｏｌ）加え、９０℃で一晩撹拌した。溶媒を留去し、酢酸エチルを抽出溶媒とし常法に従って処理し、シリカゲルクロマトグラフィーで精製し、表題化合物を得た。
収量 １．６６ｇ（２．８２ｍｍｏｌ） 収率 ６３％
Ｈ−ＮＭＲ（ＣＤＣｌ３）δ １．３３（６Ｈ，ｍ），１．４３（９Ｈ，ｓ），２．４０−２．６０（２Ｈ，ｍ），３．８５−４．２０（８Ｈ，ｍ），５．００（１Ｈ，ｂｒ），５．１３（２Ｈ，ｓ），６．００−６．５０（２Ｈ，ｍ），７．１０−７．８０（８Ｈ，ｍ）．
工程４ （４Ｓ）−５−（５−アミジノ−２−（２−（ジエトキシリン酸）エチル）フェノキシ）−４−（（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ）ペンタン酸 二トリフルオロ酢酸塩の合成
（４Ｓ）−５−（５−アミジノ−２−（２−（エトキシ（ヒドロキシ）リン酸）エチル）フェノキシ）−４−（（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ）ペンタン酸 二トリフルオロ酢酸塩の合成
行程３で得られたベンジル（４Ｓ）−４−（（ｔ−ブトキシカルボニル）アミノ）−５−（２−（（Ｅ）−２−（ジエトキシホスフォリル）エテニル）−５−エテニルフェノキシ）ペンタン酸０．４１４ｇ（０．７１ｍｍｏｌ）をジオキサン３ｍｌ、４規定塩化水素ジオキサン溶液３ｍｌに溶解し、室温で２時間撹拌した。溶媒を留去し、得られた粗製物をＮ、Ｎ−ジメチルホルムアミド（脱水）５ｍｌに溶解し、（１−ピリジン４−イル）ピペリジン−４−カルボン酸０．１６ｇ（０．７８ｍｍｏｌ）、２−クロロ−１、３−ジメチルイミダゾニウムクロライド０．１５ｇ（０．９２ｍｍｏｌ）、トリエチルアミン０．６ｍｌ（４．２ｍｍｏｌ）を加え、室温で一晩撹拌した。溶媒を留去し、得られた粗製物を実施例１の行程１１と同様の操作を行った。得られた化合物を４規定塩化水素ジオキサン溶液２．６ｍｌに溶解し、エタノール０．２６ｍｌ加え室温で一晩撹拌した。溶媒を留去し、得られた粗製物をエタノール５ｍｌに溶解し、炭酸アンモニウム０．２ｇ（３．５３ｍｍｏｌ）加え、室温で一晩撹拌した。溶媒を留去し、得られた粗製物をエタノール５ｍｌに溶解し、１０％パラジウム−炭素０．２ｇを加え、室温で水素存在下一晩撹拌した。セライト濾過し、溶媒を留去し、得られた粗製物を濃塩酸５ｍｌに溶解し、８０℃で一時間半撹拌した。溶媒を留去し、得られた粗精製物を実施例１の行程１１と同様の操作を行い表題化合物を得た。
（４Ｓ）−５−（５−アミジノ−２−（２−（ジエトキシリン酸）エチル）フェノキシ）−４−（（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ）ペンタン酸 二トリフルオロ酢酸塩
収量 ２６．７ｍｇ（０．０３２ｍｍｏｌ） 収率 ４．５％
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．２３（６Ｈ，ｂｒ），１．５０−２．１０（６Ｈ，ｍ），２．３０（２Ｈ，ｂｒ），２．５５−３．１５（６Ｈ，ｍ），３．１５−４．３０（１２Ｈ，ｍ），７．２０（２Ｈ，ｂｒ），７．３７−７．５７（２Ｈ，ｍ），８．１０（１Ｈ，ｂｒ），８．２０（２Ｈ，ｂｒ），９．１０（２Ｈ，ｂｒ），９．２０（２Ｈ，ｂｒ），９．４０（１Ｈ，ｂｒ）．
（４Ｓ）−５−（５−アミジノ−２−（２−（エトキシ（ヒドロキシ）リン酸）エチル）フェノキシ）−４−（（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ）ペンタン酸 二トリフルオロ酢酸塩
収量 ２５．５ｇ（０．０３２ｍｍｏｌ） 収率 ４．５％
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．１９（３Ｈ，ｔ），１．６０（２Ｈ，ｂｒ），１．８０−２．００（４Ｈ，ｍ），２．３０（２Ｈ，ｂｒ），２．５８−２．９５（４Ｈ，ｍ），３．００−４．３０（１０Ｈ，ｍ），７．１８（２Ｈ，ｄ），７．３８（２Ｈ，ｍ），８．０６（１Ｈ，ｄ），８．２０（２Ｈ，ｄ），９．０４（２Ｈ，ｂｒ），９．２３（３Ｈ，ｂｒ）．
行程５ （４Ｓ）−５−（５−アミジノ−２−（２−リン酸エチル）フェノキシ）−４−（（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ）ペンタン酸 二トリフルオロ酢酸塩
行程４で得られた（４Ｓ）−５−（５−アミジノ−２−（２−（エトキシ（ヒドロキシ）リン酸）エチル）フェノキシ）−４−（（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ）ペンタン酸 二トリフルオロ酢酸塩２３ｍｇ（０．０２９ｍｍｏｌ）をジオキサン５ｍｌに溶解し、トリメチルシリルブロマイド０．０３ｍｌ（０．２３ｍｍｏｌ）を加え、室温で３日間撹拌した。溶媒を留去し、得られた粗精製物を実施例１の行程１１と同様の操作を行い表題化合物を得た。
収量 １０ｍｇ（０．０１３ｍｍｏｌ） 収率 ４４％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５４８（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．６０（２Ｈ，ｂｒ），１．７０−２．００（４Ｈ，ｍ），２．３０（２Ｈ，ｂｒ），２．７０（２Ｈ，ｂｒ），２．９０（２Ｈ，ｂｒ），３．２０（２Ｈ，ｂｒ），３．４０−４．３０（６Ｈ，ｍ），７．１７（２Ｈ，ｄ），７．３７（２Ｈ，ｍ），８．１６（１Ｈ，ｄ），８．２０（２Ｈ，ｄ），９．１９（２Ｈ，ｂｒ），９．２５（２Ｈ，ｂｒ）．
実施例５ ［２−（４−ヒドロキシルアミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸 二トリフルオロ酢酸塩
工程１ ［２−（４−シアノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステル 二トリフルオロ酢酸塩の合成
［２−［（２−（２−ｔ−ブトキシカルボニルアミノ）エトキシ）−４−シアノ−フェニル］ビニル］リン酸ジエチルエステル１ｇ（２．３６ｍｍｏｌ）をジオキサン１５ｍｌ、４規定塩化水素ジオキサン溶液１５ｍｌに溶解させ、室温で２時間撹拌した。溶媒を留去して得られた粗製物をＮ、Ｎ−ジメチルホルムアミド（脱水）３０ｍｌに溶解し、１−（４−ピリジル）−４−ピペリジンカルボン酸 塩酸塩５４０ｍｇ（２．６０ｍｍｏｌ）、２−クロロ−１、３−ジメチルイミダゾニウムクロライド５２０ｍｇ（３．０７ｍｍｏｌ）、トリエチルアミン２ｍｌ（１４．２ｍｍｏｌ）を加え、一晩撹拌した。溶媒を留去し、実施例１の行程１１と同様の操作を行い表題化合物を得た。
収量 １．２０ｇ（１．９１ｍｍｏｌ） 収率 ８１％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５１３（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．２５（６Ｈ，ｔ），１．６０（２Ｈ，ｂｒ），１．９０（２Ｈ，ｂｒ），２．６０（２Ｈ，ｂｒ），３．２０（２Ｈ，ｂｒ），３．５０（２Ｈ，ｂｒ），４．００（４Ｈ，ｑ），４．２０（３Ｈ，ｂｒ），６．７５（１Ｈ，ｔ），７．１９（２Ｈ，ｄ），７．４６（１Ｈ，ｄ），７．５３−７．６８（２Ｈ，ｍ），７．９２（１Ｈ，ｄ），８．１５（１Ｈ，ｂｒ），８．２１（２Ｈ，ｄ）．
工程２ ［２−（４−シアノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸ジエチルエステル 一トリフルオロ酢酸塩の合成
行程１で得られた［２−（４−シアノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステル 一トリフルオロ酢酸塩１．２ｇ（１．９１ｍｍｏｌ）をエタノール１０ｍｌに溶解し、１０％パラジウム−炭素０．１２ｇを加え、室温で水素存在下一晩撹拌した。セライト濾過し、溶媒を留去し得られた粗精製物を実施例１の行程１１と同様の操作を行い表題化合物を得た。
収量 ２５９ｍｇ（０．４１ｍｍｏｌ） 収率 ２２％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５１５（ＭＨ＋）
行程３ ［２−（４−ヒドロキシルアミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 二トリフルオロ酢酸塩の合成
［２−（４−ヒドロキシルアミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸 二トリフルオロ酢酸塩の合成
行程２で得られた［２−（４−シアノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸ジエチルエステル 一トリフルオロ酢酸塩１２９ｍｇ（０．２０６ｍｍｏｌ）をエタノール５ｍｌに溶解し、ヒドロキシルアミン塩酸塩２２ｍｇ（０．３１ｍｍｏｌ）、トリエチルアミン０．０５ｍｌ（０．３１ｍｍｏｌ）を加え、８０℃で４時間撹拌した。溶媒を留去し得られた粗製物に濃塩酸５ｍｌを加え、８０℃で４時間撹拌した。溶媒を留去し、実施例１の行程１１と同様の操作を行い表題化合物を得た。
［２−（４−ヒドロキシルアミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸モノエチルエステル 二トリフルオロ酢酸塩
収量 ３１．４ｍｇ（０．０４２ｍｍｏｌ） 収率 ２０％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５２０（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．２０（３Ｈ，ｔ），１．５０−１．７０（２Ｈ，ｍ），１．８０−２．００（４Ｈ，ｍ），２．５５−２．７０（２Ｈ，ｍ），２．７５−２．９０（２Ｈ，ｍ），３．２０（２Ｈ，ｂｒ），３．５０（２Ｈ，ｂｒ），３．９５（２Ｈ，ｑ），４．１０（２Ｈ，ｂｒ），４．２０（１Ｈ，ｂｒ），７．１７−７．２６（３Ｈ，ｍ），７．３９（２Ｈ，ｄ），８．２０−８．３０（４Ｈ，ｍ）．
［２−（４−ヒドロキシルアミジノ−２−［２−［（１−（１−ピリジン−４−イル）ピペリジン−４−カルボニル）アミノ］エトキシ］フェニル）エチル］リン酸 二トリフルオロ酢酸塩
収量 ４．９ｍｇ（０．００７ｍｍｏｌ） 収率 ３％
ＭＳ（ＥＳＩ，ｍ／ｚ） ４９２（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．５８（２Ｈ，ｂｒ），１．８０−１．８３（４Ｈ，ｍ），２．６３（２Ｈ，ｂｒ），２．８０（２Ｈ，ｂｒ），３．１０−４．００（４Ｈ，ｍ），４．０５（２Ｈ，ｂｒ），４．１５（１Ｈ，ｂｒ），７．１５−７．２３（３Ｈ，ｍ），７．３２（２Ｈ，ｄ），８．１９（２Ｈ，ｄ），８．２９（２Ｈ，ｂｒ）．
実施例６ ［２−（４−ヒドロキシルアミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸 一トリフルオロ酢酸塩
行程１ ［２−（４−シアノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸ジエチルエステル 一トリフルオロ酢酸塩の合成
実施例３の行程１と同様の操作により得られた［２−（４−シアノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸ジエチルエステル０．８８ｇ（１．６７ｍｍｏｌ）をエタノール１０ｍｌに溶解し、１０％パラジウム−炭素０．１ｇを加え、室温で水素存在下一晩撹拌した。セライト濾過し、溶媒を留去し得られた粗精製物を実施例１の行程１１と同様の操作を行い表題化合物を得た。
収量 ６９２ｍｇ（１．３１ｍｍｏｌ） 収率 ７８％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５２８（ＭＨ＋）
行程２ ［２−（４−ヒドロキシルアミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸モノエチルエステル 一トリフルオロ酢酸塩の合成
［２−（４−ヒドロキシルアミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸 一トリフルオロ酢酸塩の合成
行程１で得られた［２−（４−シアノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）エチル］リン酸ジエチルエステル 一トリフルオロ酢酸塩０．３４ｇ（０．６６ｍｍｏｌ）をエタノール１０ｍｌに溶解し、ヒドロキシルアミン塩酸塩７０ｍｇ（０．９８ｍｍｏｌ）、トリエチルアミン０．１４ｍｌ（０．９８ｍｍｏｌ）を加え、８０℃で５時間撹拌した。溶媒を留去し得られた粗製物に濃塩酸５ｍｌを加え、８０℃で２．５時間撹拌した。溶媒を留去し、実施例１の行程１１と同様の操作を行い表題化合物を得た。
［２−（４−ヒドロキシルアミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸モノエチルエステル 一トリフルオロ酢酸塩
収量 １０３．５ｍｇ（０．１６ｍｍｏｌ） 収率 ２４％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５３３（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．１６（３Ｈ，ｔ），１．７５−２．００（６Ｈ，ｍ），２．８５（２Ｈ，ｂｒ），３．３５（２Ｈ，ｔ），３．５０（２Ｈ，ｔ），３．７０（２Ｈ，ｂｒ），３．８８（２Ｈ，ｑ），４．２５（２Ｈ，ｂｒ），７．２５（１Ｈ，ｄ），７．３０（１Ｈ，ｓ），７．３９（１Ｈ，ｄ），７．５８（２Ｈ，ｄ），７．９１（２Ｈ，ｄ），８．９０（２Ｈ，ｂｒ）．
［２−（４−ヒドロキシルアミジノ−２−［２−［４−（１−ピロリジンカルバモイル）ベンゾイルアミノ］エトキシ］フェニル）ビニル］リン酸 一トリフルオロ酢酸塩
収量 ４６．３２ｍｇ（０．０７５ｍｍｏｌ） 収率 １１％
ＭＳ（ＥＳＩ，ｍ／ｚ） ５０５（ＭＨ＋）
Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ １．７５−２．００（６Ｈ，ｍ），２．８８（２Ｈ，ｂｒ），３．３５（２Ｈ，ｔ），３．５０（２Ｈ，ｔ），３．７５（２Ｈ，ｂｒ），４．２５（２Ｈ，ｂｒ），７．２４（１Ｈ，ｄ），７．３１（１Ｈ，ｓ），７．３７（１Ｈ，ｄ），７．９１−８．００（２Ｈ，ｍ），８．９６（２Ｈ，ｍ）．
実施例７ 活性化血液凝固因子第Ｘ因子阻害活性の測定
評価化合物の水溶液１０μｌにｐＨ８．４に調整した１００ｍＭトリス−塩酸緩衝液１３０μｌを加え、次いでヒト活性化血液凝固因子第Ｘ因子（Ｅｎｚｙｍｅ Ｒｅｓｅａｒｃｈ社製）をｐＨ８．４トリス−塩酸緩衝液で０．５ユニット／ｍｌに調整した溶液１０μｌを加え、室温で１０分間インキュベートした。次いで、Ｎ−ベンゾイル−Ｌ−イソロイシン−グルタミン−グリシン−Ｌ−アルギニン−Ｐ−ニトロアニリド塩酸塩（（株）ペプチド研究所製）をｐＨ８．４トリス−塩酸緩衝液で０．８ｍＭに調整した溶液５０μｌを加え、吸光度を測定し、反応初速度を求めた。評価化合物の代わりにｐＨ８．４に調整したトリス−塩酸緩衝液１０μｌを加えたものをコントロールとした。吸光度の測定はＭＩＣＲＯＰＬＡＴＥ ＲＥＡＤＥＲ Ｍｏｄｅｌ ３５５０−ＵＶ（ＢＩＯ ＲＡＤ）を用い、４０５ｎｍの波長で１５秒間隔で１６分間測定した。評価化合物無添加の時の活性血液凝固第Ｘ因子の活性（初速度）を５０％阻害するときの評価化合物の濃度の負の対数値を求め（ｐＩＣ５０と略す）、活性化血液凝固第Ｘ因子阻害活性の指標とした。
代表的な化合物の活性化血液凝固第Ｘ因子阻害活性を下記表−１に示す。
実施例８ トロンビンの阻害活性の測定
評価化合物の水溶液１０μｌにｐＨ８．４に調整した１００ｍＭトリス−塩酸緩衝液１３０μｌを加え、次いでヒトのトロンビン（ＳＩＧＭＡ社製）をｐＨ８．４トリス−塩酸緩衝液で２ユニット／ｍｌに調整した溶液１０μｌを加え、室温で１０分間インキュベートした。次いで、Ｄ−フェニルアラニン−Ｌ−ピペコリル−Ｌ−アルギニン−Ｐ−ニトロアニリド二塩酸塩（第一化学薬品、Ｓ−２２３８）をｐＨ８．４トリス−塩酸緩衝液で０．４ｍＭに調整した溶液５０μｌを加え、吸光度を測定し、反応初速度を求めた。評価化合物の溶液の代わりにｐＨ８．４に調整したトリス−塩酸緩衝液１０μｌを加えたものをコントロールとした。吸光度の測定はＭＩＣＲＯＰＬＡＴＥ ＲＥＡＤＥＲ Ｍｏｄｅｌ ３５５０−ＵＶ（ＢＩＯ ＲＡＤ）を用い、４０５ｎｍの波長で１５秒間隔で１６分間測定した。評価化合物無添加の時のトロンビンの活性（初速度）を５０％阻害するときの評価化合物の濃度の負の対数値を求め（ｐＩＣ５０と略す）、トロンビン阻害活性の指標とした。
代表的な化合物のトロンビン阻害活性を下記表−１に示す。
実施例９ 抗血液凝固活性の測定
抗血液凝固活性はプロトロンビン時間（ＰＴ）測定法を用いて決定した。ＰＴ測定は以下に示す通りに行った。すなわち、健常人より採血を行い、３．８％クエン酸三ナトリウム水溶液を１０分の１容量加え、遠心操作により血漿を分離した。血漿４５μｌに評価化合物を含むＤＭＳＯ溶液５μｌを加え、室温で２分間インキュベートした。その血漿溶液を含む試験管をＳｙｓｍｅｘ ＣＡ−３０００全自動血液凝固測定装置（東亜医用電子社）に設置後、３７℃で３分間インキュベートし、Ｓｙｓｍｅｘ ＰＴ ＩＩ（東亜医用電子社、ウサギ脳組織トロンボプラスチン、１３．２ｍＭ塩化カルシウム）１００μｌを加えた。ＰＴは同装置により自動測定した。評価化合物の溶液の代わりにＤＭＳＯ５μｌを加えたものをコントロールとし、コントロールのＰＴを２倍に延長する評価化合物濃度の負の対数値を求め（ｐＰＴ２と略す）、抗血液凝固活性の指標とした。

また、実施例１記載の化合物（式（２−１）で示される化合物）は、優れた抗血液凝固活性も示した（ｐＰＴ２＝６．８）。
この結果により本発明のベンズアミジン誘導体は、活性化血液凝固因子第Ｘ因子に特異的な高い阻害活性を示し、これに基づく高い抗凝固活性を示すことがわかった。以下実施例で述べた本発明化合物の構造式を示す。

本発明化合物またはその塩を有効成分とする抗凝固剤は優れた活性化血液凝固第Ｘ因子阻害作用に基づく抗血液凝固作用を示す。従って、本発明化合物は脳梗塞、脳卒中、脳血栓、脳塞栓、一過性脳虚血発作（ＴＩＡ）、くも膜下出血（血管れん縮）等の脳血管障害における疾病、急性及び慢性心筋梗塞、不安定狭心症、冠動脈血栓等の虚血性心疾患における疾病、肺梗塞、肺塞栓等の肺血管障害における疾病、末梢動脈閉塞症、深部静脈血栓症、汎発性血管内凝固症候群、さらに人工血管術及び人工弁置換後の血栓形成、冠動脈バイパス術後における再閉塞及び再狭窄、経皮的経管式冠動脈形成術（ＰＴＣＡ）または経皮的経管式冠動脈再開通療法（ＰＴＣＲ）等の血行再建後の再閉塞及び再狭窄、体外循環時の血栓形成などの予防・治療剤として利用できる。Background of the Invention
The present invention is caused by a novel orally administrable benzamidine derivative that reversibly inhibits activated blood coagulation factor X and exhibits a strong anticoagulant action, and a blood coagulation inhibitor or thrombus or embolus containing them as an active ingredient The present invention relates to a preventive / therapeutic agent for diseases. Examples of the applicable diseases include cerebral vascular disorders such as cerebral infarction, stroke, cerebral thrombus, cerebral embolism, transient cerebral ischemic attack (TIA), subarachnoid hemorrhage (vasospasm), acute and chronic myocardial infarction, Stable angina, diseases in ischemic heart diseases such as coronary thrombus, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation syndrome, and artificial blood vessels Blood flow such as thrombus formation after surgery and prosthetic valve replacement, reocclusion and restenosis after coronary artery bypass grafting, percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary artery recanalization (PTCR) Examples include re-occlusion and restenosis after reconstruction, and thrombus formation during extracorporeal circulation.
Thromboembolic diseases such as myocardial infarction, cerebral thrombosis, and peripheral arterial thrombosis tend to increase year by year as the lifestyles become westernized and the population ages, and the social importance of treatment is increasing It is growing. Anticoagulant therapy is part of a medical therapy in the treatment and prevention of thrombosis along with fibrinolysis and antiplatelet therapy.
Conventionally, antithrombin agents have been developed as thrombus formation inhibitors, but thrombin not only controls the activation of fibrinogen, which is the final stage of the coagulation reaction, but also deeply activates and aggregates platelets. Because of its involvement, its inhibition was known to be at risk of bleeding tendency. Moreover, the bioavailability of oral administration is low, and no thrombin inhibitor that can be administered orally has been marketed.
Activated blood coagulation factor X is located at the confluence of extrinsic and intrinsic coagulation cascade reactions and is located upstream of thrombin, so that inhibition of this factor is more efficient and specific than thrombin inhibition May inhibit the system [Tidwell, R .; Webster, W .; P. Shaver, S .; R. Geratz, J .; D. THROMBOSIS RESEARCH Vol. 19, 339-349, 1980].
So far, benzamidine derivatives that selectively inhibit activated blood coagulation factor X have been disclosed (for example, WO9831661, WO99664392), but have further excellent activated blood coagulation factor X inhibitory action and excellent There is a strong demand for drugs having anticoagulant action.
Disclosure of the invention
An object of the present invention is to provide a compound having an excellent activated blood coagulation factor X inhibitory action.
It is an object of the present invention to provide a compound having an inhibitory action specific to activated blood coagulation factor X that can be administered orally.
An object of the present invention is to provide an anticoagulant or a prophylactic or therapeutic agent for thrombus or embolus containing the above compound.
The present invention also includes a disease in a cerebrovascular disorder, a disease in an ischemic heart disease, a disease in a pulmonary vascular disorder, a peripheral arterial occlusion, a deep vein thrombosis, a generalized intravascular coagulation syndrome, an artificial blood vessel. The purpose is to provide a prophylactic / therapeutic agent for thrombus formation after surgery and prosthetic valve replacement, reocclusion and restenosis after coronary artery bypass surgery, reocclusion and restenosis after revascularization, and thrombus formation during extracorporeal circulation .
Another object of the present invention is to provide a pharmaceutical composition containing the above compound.
As a result of various studies in view of the above-mentioned circumstances, the present inventors have found that a specific novel benzamidine derivative having a phosphonoethyl group has a particularly excellent activated blood coagulation factor X inhibitory action, The present invention has been found to be useful as a preventive and therapeutic agent for other diseases, and the present invention has been completed. For example, the compound represented by the formula (2-1) described below exhibits excellent activated blood coagulation factor X inhibitory activity (pIC50 = 8.5) and does not exhibit thrombin inhibitory activity (pIC50 = <3.5). , Showed a selective activated blood coagulation factor X inhibitory action.
In addition, the compound represented by the formula (2-1) also showed an excellent anticoagulant activity (pPT2 = 6.8).
That is, the present invention provides a benzamidine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt, and an anticoagulant containing them as an active ingredient.

[Wherein, X is a hydrogen atom, a carboxyl group, an alkoxycarbonyl group having 2 to 4 carbon atoms, an optionally substituted alkyl group having 1 to 3 carbon atoms, or an optionally substituted benzyl group. Where the substituent in the case of having a substituent represents either a carboxyl group or an alkoxycarbonyl group having 2 to 8 carbon atoms,
V represents either a benzoyl group or a piperidinecarbonyl group which may have a substituent, and in the case of having a substituent, the substituent is an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, or 6 to 6 carbon atoms. It represents any of 10 aryl groups, heteroaryl groups having 4 to 5 carbon atoms, carbamoyl groups, and mono- or dialkylcarbamoyl groups having 2 to 7 carbon atoms. ]
BEST MODE FOR CARRYING OUT THE INVENTION
In the present specification, an alkyl group as a component such as an alkyl group, an alkoxycarbonyl group, or an iminoalkylpiperidyloxy group may contain a branch or a ring. Examples of the alkyl group include alkyl groups having 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cyclopropyl group. Examples of the alkoxycarbonyl group include C2-C10, preferably C2-C8 alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, benzyloxycarbonyl group, and the like, and iminoalkylpiperidyloxy group Examples thereof include those having 7 to 10 carbon atoms such as 1-acetimidoyl-4-piperidyloxy group.
Examples of the aryl group in the present specification include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and the like, and the heteroaryl group is an aromatic having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. A heterocyclic group is preferred, and examples thereof include a pyridyl group, a pyrimidyl group, a pyridazinyl group, and a pyrazinyl group.
In the dialkylcarbamoyl group in the present specification, two alkyl groups may be bonded to form a ring. At this time, the methylene group may be substituted with an oxygen atom, an amino group, or a sulfur atom. Examples thereof include 1-pyrrolidinecarbonyl group, 1-piperidinecarbonyl group, 1-piperazinecarbonyl group, 1-morpholinecarbonyl group and the like.
In the general formula (1), the group represented by X is preferably a hydrogen atom, a carboxymethyl group, or a carboxyethyl group.
As the group represented by V, V represents either a benzoyl group or a piperidinecarbonyl group which may have a substituent. Here, the substituent in the case of having a substituent is an imino having 7 to 10 carbon atoms. An alkylpiperidyloxy group, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 4 to 5 carbon atoms, a carbamoyl group, or a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms is preferable. Among these, as the group represented by V, 1-acetimidoyl-4-piperidyloxybenzoyl group, 1- (4-pyridyl) -piperidine-4-carbonyl group, 4- (1-pyrrolidinecarbonyl) benzoyl group Is preferred.
Moreover, the compound of the formula (2-1)-(2-6) shown below, or its pharmaceutically acceptable salt is preferable.

The benzamidine derivative (1) of the present invention can be produced by using the following method. For example, general formula (1-1) is produced as follows.
That is, for example, aminoalkyl halide (3) protected on nitrogen with, for example, a benzyloxycarbonyl group or t-butoxycarbonyl group, and using, for example, dimethylformamide as a solvent, for example, 3-hydroxy-4-in the presence of a base such as potassium carbonate. By reacting iodobenzonitrile (4), iodobenzonitrile derivative (5) can be obtained. The obtained iodobenzonitrile derivative (5) can be led to the phosphoric acid diester derivative (6) by using, for example, Heck reaction or the like using, for example, dimethylformamide as a solvent. The protecting group on the nitrogen of the obtained phosphoric acid diester derivative (6) can be deprotected in an acidic solution such as a 4N hydrogen chloride dioxane solution to obtain the amine (7).

Subsequently, dimethylformamide or the like is used as a solvent, and a condensation agent is allowed to act on amine (7) in the presence of a base such as triethylamine, whereby condensation with carboxylic acid is performed to obtain amide (8). it can. The obtained amide (8) is reacted with an alcohol such as ethanol containing hydrogen halide such as hydrogen chloride, and then reacted with an ammonium salt such as ammonium carbonate to convert the cyano group into an amidino group. To obtain an amidine derivative (9). For the amidine derivative (9), for example, an alcohol such as methanol is used as a solvent, and the reaction is performed in a hydrogen atmosphere in the presence of a catalyst such as barium carbon, followed by hydrolysis with an acidic aqueous solution such as concentrated hydrochloric acid. Thus, the benzamidine derivative (1-1) can be produced.

The compounds represented by the general formulas (1) to (2-6) and salts thereof thus produced are separated and purified by known means such as extraction, concentration, vacuum concentration, solvent extraction, crystallization, and recrystallization. , And can be isolated and purified by dissolution, various types of chromatography, and the like.
Since the benzamidine derivative represented by the general formula (1) of the present invention may have an asymmetric carbon, an optically active form is also conceivable. However, the compound shown in the present invention is a mixture or isolated of this optically active form. Also included.
The amidino group in the compound of the present invention may be substituted by an appropriate substitution that is exchanged with an amidino group in vivo. For example, in the general formula (1), a hydrogen atom bonded to a nitrogen atom having a double bond of an amidino group bonded to a benzene ring is a hydroxyl group, an alkoxyl group such as an ethoxy group, an amino group, a carboxyl group Group, alkoxycarbonyl group such as ethoxycarbonyl group, alkylsulfonyl group such as ethylsulfonyl group, carbamoyl group, carbamoyl group such as carbamoyl group, diethoxycarbamoyl group, substituted with alkyl group, formyl group And those substituted with an acyl group such as an acetyl group and an alkyl carboxyl group such as an acetoxy group. Examples of the compound of the present invention substituted with such a group include compounds represented by formulas (2-5) and (2-6).
The salt of the benzamidine derivative represented by the general formulas (1) to (2-6) of the present invention may be any pharmaceutically acceptable salt, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. Mineral acids such as formic acid, acetic acid, trifluoroacetic acid, lactic acid, salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, tosylic acid, methanesulfonic acid, benzenesulfonic acid And acid addition salts with organic acids such as
The compounds represented by the general formulas (1) to (2-6) or salts thereof are administered as they are or as various pharmaceutical compositions. The dosage form of such a pharmaceutical composition may be, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, dragees, or devoted drugs, using ordinary formulation aids. Can be manufactured according to conventional methods. For example, tablets may contain benzamidine derivatives, which are active ingredients of the present invention, known auxiliary substances such as lactose, inert diluents such as calcium carbonate or calcium phosphate, binders such as gum arabic, corn starch or gelatin, alginic acid, corn starch or the like It is obtained by mixing with a swelling agent such as gelatinized starch, a sweetener such as sucrose, lactose or saccharin, a flavoring agent such as peppermint or cherry, and a lubricant such as magnesium stearate, talc or carboxymethylcellulose.
When the benzamidine derivative represented by the general formulas (1) to (2-6) is used as an anticoagulant, the route of administration may be either oral or parenteral, and the dosage is the age and weight of the patient. The dose per day for an adult is usually 0.01 to 1000 mg, preferably 0.1 to 50 mg in the case of oral administration, and is different from that in the case of parenteral administration. 1 μg to 100 mg, preferably 0.01 to 10 mg.
An anti-coagulant containing the compound represented by the general formula (1) to formula (2-6) or a salt thereof as an active ingredient or a prophylactic / therapeutic agent for diseases caused by thrombus or embolism is, for example, cerebral infarction, stroke, cerebral thrombus Cerebral embolism, transient cerebral ischemic attack (TIA), diseases in cerebrovascular disorders such as subarachnoid hemorrhage (vasospasm), ischemic heart such as acute and chronic myocardial infarction, unstable angina pectoris, coronary artery thrombus Diseases in diseases, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation syndrome, thrombus formation after artificial vascular surgery and valve replacement, coronary artery bypass Re-occlusion and restenosis after surgery, re-occlusion and restenosis after revascularization such as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary artery recurrent therapy (PTCR), during extracorporeal circulation Thrombus formation It can be used as a preventive and therapeutic agent.
The following examples illustrate the invention in detail. These are preferred embodiments of the present invention, but the present invention is not limited to these examples.
Example 1 [2- (4-Amidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphate ditrifluoroacetate
Step 1 Synthesis of ethyl 1- (4-pyridyl) -4-piperidinecarboxylate
4.0 g (26.6 mmol) of 4-chloropyridine hydrochloride, 4.2 g (26.6 mmol) of ethyl piperidine-4-carboxylate, and 7.4 ml (53.2 mmol) of triethylamine were stirred in 130 ml of xylene at 130 ° C. for 24 hours. did. The crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 2.95 g (12.6 mmol) Yield 47%
H-NMR (CDCl3) δ 1.25 (3H, t), 1.71-1.85 (2H, m), 2.00 (2H, d), 2.50-2.60 (1H, m) , 2.90 (2H, t), 3.81 (2H, d), 4.20 (2H, q), 6.66 (2H, d), 8.26 (2H, d)
Step 2 Synthesis of 1- (4-pyridyl) -4-piperidinecarboxylic acid hydrochloride
2.95 g (12.6 mmol) of ethyl 1- (4-pyridyl) -4-piperidinecarboxylate was stirred in 100 ml of dioxane, 50 ml of 1N hydrochloric acid was added, and the mixture was stirred at 95 ° C. for 20 hours. The solvent was distilled off to give a crude product of the title compound.
Yield 3.21 g (11.5 mmol) Yield 91%
H-NMR (DMSO-d6) δ 1.54 (2H, t), 1.90 (2H, t), 2.60-2.70 (1H, m), 3.30 (2H, t), 4 .10 (2H, d), 7.19 (2H, d), 8.20 (2H, d)
Step 3 Synthesis of 3-hydroxy-4-iodobenzoic acid
30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid, and 53.0 g (326 mmol) of iodine monochloride was added at room temperature. After stirring at 45 ° C. for 15 hours, the residue obtained by distilling off the solvent under reduced pressure was washed twice with 500 ml of 1% aqueous sodium thiosulfate solution and twice with 500 ml of water, and dried at 80 ° C. under reduced pressure to give the title compound. Got.
Yield 17.2 g (65.2 mmol) Yield 30%
MS (FAB, m / z) 265 (MH +)
H-NMR (DMSO-d6) δ 7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
Step 4 Synthesis of 3-hydroxy-4-iodobenzonitrile
To a solution of 22.3 g (89.7 mmol) of 3-hydroxy-4-iodobenzoic acid in 300 ml of tetrahydrofuran, 19.7 ml (206 mmol) of ethyl chloroformate and 28.7 ml (206 mmol) of triethylamine were added at 0 ° C. After stirring for 15 minutes, the produced triethylamine hydrochloride was filtered off, and the filtrate was added at 0 ° C. to 300 ml of a tetrahydrofuran solution obtained by bubbling ammonia. After stirring at room temperature for 10 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 450 ml of dioxane, and 17.4 ml (117 mmol) of trifluoromethanesulfonic anhydride and 21.8 ml (269 mmol) of pyridine were added at 0 ° C. . After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, and the resulting residue was treated according to a conventional method using chloroform as an extraction solvent to obtain an oily residue. To a solution of the obtained residue in 180 ml of tetrahydrofuran: methanol (1: 1), 1N aqueous sodium hydroxide solution (90 ml, 90.0 mmol) was added at room temperature. After stirring for 4 hours, the solvent was distilled off under reduced pressure, and the resulting residue was washed with dichloromethane. Subsequently, the mixture was acidified with 1N hydrogen chloride and treated according to a conventional method using ethyl acetate as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 9.29 g (37.9 mmol) Yield 42%
MS (FAB, m / z) 246 (MH +)
H-NMR (CDCl3) δ 5.63 (1H, br), 6.96 (1H, dd), 7.23 (1H, d), 7.79 (1H, d)
Step 5 Synthesis of t-butyl (2-bromoethyl) carbamate
2-Bromoethylamine hydrobromide 9.22 g (45 mmol) was dissolved in 100 ml of dichloromethane, and 7.64 g (35 mmol) of di-t-butyl dicarbonate, 10.0 g (99 mmol) of triethylamine, 4- (dimethylamino) 100 mg (0.82 mmol) of pyridine was added and stirred overnight. The title compound was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent.
Yield 5.99 g (26.7 mmol) Yield 76%
H-NMR (CDCl3) δ 1.45 (9H, s), 3.46 (2H, dt), 3.51 (2H, t), 4.95 (1H, br)
Step 6 Synthesis of 3- [2- (t-butoxycarbonylamino) ethoxy) -4-iodobenzonitrile
18.5 g (82.6 mmol) of t-butyl (2-bromoethyl) carbamate was dissolved in 200 ml of DMF, 10.1 g (41.3 mmol) of 3-hydroxy-4-iodobenzonitrile, 5.7 g (41.3 mmol) of potassium carbonate. ) And stirred at 75 ° C. for 3 hours. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent.
Yield 11.0 g (28.4 mmol) Yield 69%
H-NMR (CDCl3) δ 1.46 (9H, s), 3.62 (2H, dt), 4.12 (2H, t), 7.02 (2H, d), 7.88 (2H, d ).
Step 7 Synthesis of 2- (2- (t-butoxycarbonylamino) ethoxy) -4-cyano-benzoic acid methyl ester
3- (2- (t-butoxycarbonylamino) ethoxy) -4-iodobenzonitrile (5 g, 12.88 mmol) was dissolved in 60 ml of N, N-dimethylformamide (dehydrated), and 3.6 ml (25.8 mmol) of triethylamine was dissolved. , 10 ml (25.8 mmol) of methanol and 145 mg (0.644 mmol) of palladium acetate were added, and the mixture was stirred at 90 ° C. for 6 hours in the presence of carbon monoxide. The solvent was distilled off and ethyl acetate was used as an extraction solvent, followed by a conventional process to obtain a crude product. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 4.11 g (12.82 mmol) Yield 99.5%
H-NMR (CDCl3) δ 1.44 (9H, s), 3.61 (2H, q), 3.94 (3H, s), 4.12 (2H, m), 5.38 (1H, br) ), 7.21 (1H, s), 7.38 (1H, m), 7.87 (1H, d).
Step 8 Synthesis of 3- (2- (t-butoxycarbonylamino) ethoxy) -4-hydroxymethylbenzonitrile
Dissolve 4.15 g (12.95 mmol) of 2- (2- (t-butoxycarbonylamino) ethoxy) -4-cyano-benzoic acid methyl ester in 60 ml of tetrahydrofuran (dehydrated), and 2M lithium borohydride under ice cooling. 6 ml (17.2 mmol) was added and stirred overnight at room temperature. The solvent was distilled off and ethyl acetate was used as an extraction solvent, followed by a conventional process to obtain a crude product. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 2.38 g (8.12 mmol) Yield 63%
H-NMR (CDCl3) δ 1.41 (9H, s), 3.00 (1H, br), 3.60 (2H, br), 4.10 (2H, t), 4.70 (2H, d ), 4.95 (1H, br), 7.07 (1H, s), 7.30 (1H, d), 7.41 (1H, d).
Step 9 Synthesis of 3- (2- (t-butoxycarbonylamino) ethoxy) -4-formylbenzonitrile
3- (2- (t-butoxycarbonylamino) ethoxy) -4-hydroxymethylbenzonitrile (0.3 g, 1.03 mmol) was dissolved in dichloromethane (dehydrated) (3 ml), and activated manganese dioxide (0.36 g, 4.1 mmol) was dissolved. ) In the presence of argon and stirred overnight at room temperature. The reaction solution was filtered through Celite to obtain the title compound.
Yield 279 mg (0.962 mmol) Yield 93%
MS (ESI, m / z) 291 (MH-)
H-NMR (CDCl3) δ 1.53 (9H, s), 3.62 (2H, q), 4.20 (2H, t), 4.95 (1H, br), 7.35 (2H, m ), 7.93 (1H, d), 10.50 (1H, s).
Step 10 Synthesis of [2-[(2- (2-t-butoxycarbonylamino) ethoxy) -4-cyano-phenyl] vinyl] phosphoric acid diethyl ester
Tetraethylmethylene diphosphonate (0.54 ml, 2.18 mmol) was dissolved in tetrahydrofuran (dehydrated) (10 ml), and 1.54 Mn-butyllithium hexane solution (1.5 ml, 1.0 mmol) was added at -78 ° C. in the presence of argon for 20 minutes. After stirring, 527 mg (1.82 mmol) of 3- (2- (t-butoxycarbonylamino) ethoxy) -4-formylbenzonitrile was added, and the mixture was stirred at -78 ° C. for 45 minutes, then warmed to room temperature and stirred for 3 hours. The solvent was distilled off, and the residue was treated according to a conventional method using dichloromethane as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 0.45 g (1.06 mmol) Yield 58%
H-NMR (CDCl3) δ 1.17-1.42 (6H, m), 1.47 (9H, s), 3.60 (2H, br), 3.96-4.23 (6H, m) , 5.00 (1H, br), 6.40 (2H, m), 7.15 (1H, s), 7.27 (1H, d), 7.58 (1H, d).
Step 11 [2- (4-Amidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) vinyl] phosphoric acid diethyl ester ditrifluoroacetic acid Salt synthesis
[2- (4-Amidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) vinyl] phosphoric acid monoethyl ester ditrifluoroacetate Composition
[2-[(2- (2-t-Butoxycarbonylamino) ethoxy) -4-cyano-phenyl] vinyl] phosphoric acid diethyl ester 0.45 g (1.06 mmol) in dioxane 5 ml, 4N hydrogen chloride dioxane solution 5 ml And stirred at room temperature for 3 hours. The crude product obtained by distilling off the solvent was dissolved in 10 ml of N, N-dimethylformamide (dehydrated), 0.29 g (1.2 mmol) of 1- (4-pyridyl) -4-piperidinecarboxylic acid hydrochloride, 2-Chloro-1,3-dimethylimidazolium chloride 0.5 g (2.8 mmol) and triethylamine 1.8 ml (12.8 mmol) were added and stirred overnight. The crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. The obtained crude product was dissolved in 5 ml of 4N hydrogen chloride dioxane solution and 0.5 ml of ethanol and stirred at room temperature for 3 days. The residue obtained by distilling off the solvent was dissolved in 5 ml of ethanol, 0.19 g (3.35 mmol) of ammonium carbonate was added, and the mixture was stirred overnight at room temperature. The crude product obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% of trifluoroacetic acid (v / v) water. The title compound was obtained by elution with a mixed solvent of ethanol and acetonitrile and freeze-drying the target fraction.
[2- (4-Amidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) vinyl] phosphoric acid diethyl ester ditrifluoroacetate
Yield 155 mg (0.204 mmol) Yield 31%
MS (ESI, m / z) 530 (MH +)
H-NMR (DMSO-d6) δ 1.26 (6H, t), 1.50-1.92 (4H, m), 2.58 (2H, br), 3.22 (2H, t), 3 .50 (2H, br), 4.03 (4H, m), 4.20 (3H, br), 6.77 (2H, m), 7.19 (2H, d), 7.40-7. 74 (3H, m), 7.96 (1H, d), 8.21 (2H, d), 9.33 (2H, br), 9.36 (2H, br).
[2- (4-Amidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) vinyl] phosphoric acid monoethyl ester ditrifluoroacetate Composition
Yield 63.4 mg (0.087 mmol) Yield 13%
MS (ESI, m / z) 502 (MH +)
H-NMR (DMSO-d6) δ 1.23 (3H, t), 1.50-1.95 (4H, m), 2.58 (2H, br), 3.22 (2H, t), 3 .50 (2H, br), 3.95 (2H, m), 4.22 (3H, br), 6.71 (2H, m), 7.18 (2H, d), 7.38-7. 66 (3H, m), 7.92 (1H, d), 8.20 (2H, d), 9.21 (2H, br), 9.34 (2H, br).
Step 12 [2- (4-Amidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphoric acid monoethyl ester ditrifluoro Synthesis of acetate
[2- (4-Amidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) vinyl] phosphoric acid monoethyl ester ditrifluoroacetate 63.4 mg (0.087 mmol) g was dissolved in 2 ml of ethanol, 10 mg of palladium-carbon (containing 50% water) was added under argon, and the mixture was stirred overnight at room temperature in the presence of hydrogen. The title compound was obtained in the same manner as in Example 1, Step 11 by adding 2 ml of water and distilling off the solvent.
Yield 43.1 mg (0.059 mmol) Yield 68%
MS (ESI, m / z) 504 (MH +)
H-NMR (DMSO-d6) δ 1.20 (3H, t), 1.58 (2H, br), 1.80-1.96 (4H, m), 2.62 (2H, br), 2 .80 (2H, br), 3.21 (2H, t), 3.49 (2H, q), 3.88-3.98 (2H, m), 4.12 (2H, t), 4. 20 (1H, br), 7.18 (2H, d), 7.37-7.42 (3H, m), 8.21 (2H, d), 8.28 (1H, br), 9.18 (2H, br), 9.25 (2H, br).
Step 13 [2- (4-Amidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphoric acid ditrifluoroacetate
[2- (4-Amidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphoric acid monoethyl ester ditrifluoroacetate 27.5 mg (37.59 mmol) g was dissolved in 2 ml of concentrated hydrochloric acid and stirred at 80 ° C. for 11 hours. The title compound was obtained from the crude product obtained by distilling off the solvent by the same procedure as in Step 1 of Example 1.
Yield 9 mg (12.79 mmol) Yield 34%
MS (ESI, m / z) (MH +) 476
H-NMR (DMSO-d6) δ 1.50-2.20 (6H, m), 2.69 (2H, br), 2.83 (2H, br), 3.14-3.36 (2H, m), 3.49 (2H, br), 4.07-4.26 (3H, m), 7.14-7.24 (3H, m), 7.32-7.44 (2H, m) , 8.21 (2H, d), 8.34 (1H, br), 9.23 (3H, br).
Example 2 [2- (4-Amidino-2- [2- [4- (1- (1-acetimidoyl) -4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid ditrifluoroacetic acid salt
Step 1 Synthesis of [2-[(2- (2-t-butoxycarbonylamino) ethoxy) -4-cyano-phenyl] vinyl] phosphoric acid diethyl ester
10 g (25.76 mmol) of 3- (2- (t-butoxycarbonylamino) ethoxy) -4-iodobenzonitrile was dissolved in 100 ml of N, N-dimethylformamide (dehydrated), and 4.75 ml (30. 91 mmol), 58 mg (0.258 mmol) of palladium acetate and 160 mg (0.515 mmol) of tris (2-methylphenyl) phosphine were added, and the mixture was stirred at 100 ° C. overnight. The solvent was distilled off, and the residue was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 9.46 g (22.3 mmol) Yield 87%
H-NMR (CDCl3) δ 1.38 (6H, t), 2.15 (2H, br), 3.60 (2H, br), 4.11 (4H, m), 5.18 (1H, br ), 6.40 (1H, t), 7.13 (1H, s), 7.29 (1H, m), 7.58 (1H, d), 7.72-7.86 (1H, m) .
Step 2 [2- (4-Amidino-2- [2- [4- (4-piperidyloxy) benzoylamino] ethoxy] phenyl) vinyl] phosphoric acid diethyl ester Synthesis of ditrifluoroacetate
[2-[(2- (2-t-Butoxycarbonylamino) ethoxy) -4-cyano-phenyl] vinyl] phosphoric acid diethyl ester 1.5 g (3.53 mmol) in dioxane 15 ml, 4N hydrogen chloride dioxane solution 15 ml And stirred at room temperature for 2 hours. The crude product obtained by distilling off the solvent was dissolved in 10 ml of N, N-dimethylformamide (dehydrated), and 1.25 g (3.88 mmol) of 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoic acid was dissolved. ), 0.78 g (4.59 mmol) of 2-chloro-1,3-dimethylimidazolium chloride, and 3 ml (21.2 mmol) of triethylamine were added and stirred for 4 hours, and the solvent was distilled off. The obtained crude product was dissolved in 50 ml of 4N hydrogen chloride dioxane solution, 5 ml of ethanol was added, and the mixture was stirred overnight at room temperature. The residue obtained by distilling off the solvent was dissolved in 10 ml of ethanol, 1 g (17.65 mmol) of ammonium carbonate was added, and the mixture was stirred overnight at room temperature. The crude product obtained by distilling off the solvent was dissolved in 30 ml of dioxane and 30 ml of 4N hydrogen chloride dioxane solution and stirred at room temperature for 2 hours. The title compound was obtained from the crude product obtained by evaporating the solvent by the same procedure as in Step 1 of Example 1.
Yield 1.45 g (1.88 mmol) Yield 53%
Step 3 [2- (4-Amidino-2- [2- [4- (1- (1-acetimidoyl) -4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid diethyl ester ditrifluoro Synthesis of acetate
[2- (4-Amidino-2- [2- [4- (4-piperidyloxy) benzoylamino] ethoxy] phenyl) vinyl] phosphoric acid diethyl ester obtained in step 2 1.45 g of ditrifluoroacetate ( 1.88 mmol) was dissolved in 50 ml of ethanol, and 0.695 g (5.65 mmol) of ethylacetimidate hydrochloride and 1.31 ml (9.38 mmol) of triethylamine were added and stirred overnight. The crude product obtained by distilling off the solvent was dissolved in 50 ml of ethanol, 150 mg of 10% palladium-carbon was added, and the mixture was stirred overnight in the presence of hydrogen. The mixture was filtered through Celite, the solvent was distilled off, and the obtained crude product was subjected to the same operation as in Step 11 of Example 1 to obtain the title compound.
Yield 98 mg (0.12 mmol) Yield 6%
MS (ESI, m / z) 588 (MH +)
H-NMR (DMSO-d6) δ 1.17 (6H, t), 1.80 (2H, br), 1.95-2.20 (4H, m), 2.30 (3H, s), 2 .85 (2H, br), 3.40-3.80 (6H, m), 3.90 (4H, q), 4.25 (2H, br), 4.80 (1H, br), 7. 06 (2H, d), 7.42 (3H, m), 7.86 (2H, d), 8.60 (2H, br), 9.11 (3H, br), 9.26 (2H, br) ).
Step 4 [2- (4-Amidino-2- [2- [4- (4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphate monoethyl ester Synthesis of ditrifluoroacetate
Synthesis of [2- (4-amidino-2- [2- [4- (4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphate ditrifluoroacetate
[2- (4-cyano-2- [2- [4- (1- (1-t-butoxycarbonyl) -4-piperidyloxy) benzoylamino] ethoxy] phenyl) obtained from the same procedure as in step 2 Vinyl] phosphoric acid diethyl ester 0.3 g (0.478 mmol) was dissolved in ethanol 30 ml, 10% palladium-carbon 30 mg was added, and the mixture was stirred overnight in the presence of hydrogen. The crude product obtained by filtering through Celite and removing the solvent was dissolved in 10 ml of dioxane and 10 ml of 4N hydrogen chloride dioxane solution, and the mixture was stirred at room temperature for 1 hour. The crude product obtained by distilling off the solvent was dissolved in 30 ml of 4N hydrogen chloride dioxane solution, 3 ml of ethanol was added, and the mixture was stirred overnight at room temperature. The residue obtained by distilling off the solvent was dissolved in 10 ml of ethanol, 0.2 g (3.5 mmol) of ammonium carbonate was added, and the mixture was stirred overnight at room temperature. The crude product obtained by distilling off the solvent was dissolved in 5 ml of concentrated hydrochloric acid and stirred at 80 ° C. for 4 hours. The title compound was obtained by evaporating the solvent and conducting the same procedure as in Step 11 of Example 1.
[2- (4-Amidino-2- [2- [4- (4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid monoethyl ester ditrifluoroacetate
Yield 53.2 mg (0.07 mmol) Yield 15%
MS (ESI, m / z) 519 (MH +)
H-NMR (DMSO-d6) δ 1.16 (3H, t), 1.75-2.00 (4H, m), 2.10 (2H, br), 2.85 (2H, br), 3 .10 (2H, br), 3.25 (2H, br), 3.60-4.00 (4H, m), 4.20 (2H, br), 4.75 (1H, br), 7. 05 (2H, d), 7.41 (3H, m), 7.86 (2H, d), 8.60 (2H, m), 9.10 (2H, br), 9.25 (2H, br) ).
[2- (4-Amidino-2- [2- [4- (4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid
Yield 6.96 mg (0.0096 mmol) Yield 2%
MS (ESI, m / z) 491 (MH +)
H-NMR (DMSO-d6) δ 1.80 (4H, br), 2.10 (2H, br), 2.95 (2H, br), 3.00-3.75 (6H, m), 4 .20 (2H, br), 4.70 (1H, br), 7.05 (2H, d), 7.40 (3H, m), 7.88 (2H, d), 8.56 (1H, br), 8.74 (1H, br), 9.06 (2H, br), 9.22 (2H, br).
Step 5 [2- (4-Amidino-2- [2- [4- (1- (1-acetimidoyl) -4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid monoethyl ester Nitri Synthesis of fluoroacetates
[2- (4-Amidino-2- [2- [4- (4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid monoethyl ester obtained in step 4 ditrifluoroacetate salt 46.94 mg (0.063 mmol) was dissolved in 5 ml of ethanol, 75 mg (0.57 mmol) of ethylacetimidate hydrochloride and 0.15 ml (0.945 mmol) of triethylamine were added, and the mixture was stirred overnight. The title compound was obtained by evaporating the solvent and conducting the same procedure as in Step 11 of Example 1.
Yield 34.26 mg (mmol) Yield 69%
MS (ESI, m / z) 560 (MH +)
H-NMR (DMSO-d6) δ 1.16 (3H, t), 1.70-2.00 (4H, m), 2.10 (2H, br), 2.30 (3H, s), 2 .85 (2H, m), 3.50 (2H, m), 3.60-3.80 (4H, m), 3.88 (2H, q), 4.20 (2H, br), 4. 80 (1H, br), 7.06 (2H, d), 7.41 (3H, m), 7.86 (2H, d), 8.60 (1H, br), 8.66 (1H, br) ), 9.13 (3H, br), 9.24 (2H, br).
Step 6 [2- (4-Amidino-2- [2- [4- (1- (1-acetimidoyl) -4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphate ditrifluoroacetate
[2- (4-Amidino-2- [2- [4- (4-piperidyloxy) benzoylamino] ethoxy] phenyl) ethyl] phosphate obtained in Step 4 6.96 mg (0. 0096 mmol) was dissolved in 5 ml of ethanol, 14 mg (0.086 mmol) of ethylacetimidate hydrochloride and 0.03 ml (0.144 mmol) of triethylamine were added and stirred overnight. The title compound was obtained by evaporating the solvent and conducting the same procedure as in Step 11 of Example 1.
Yield 4.87 mg (0.0064 mmol) Yield 67%
MS (ESI, m / z) 532 (MH +)
H-NMR (DMSO-d6) δ 1.70-1.90 (4H, m), 2.10 (2H, br), 2.30 (3H, s), 2.85 (2H, br), 2 .65 (2H, br), 3.60-3.85 (4H, m), 4.20 (2H, br), 4.80 (1H, br), 7.06 (2H, d), 7. 40 (3H, m), 7.87 (2H, d), 8.60 (1H, br), 8.72 (1H, br), 9.08 (2H, br), 9.16 (1H, br) ), 9.22 (2H, br).
Example 3 [2- (4-Amidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid monotrifluoroacetate
Step 1 Synthesis of [2- (4-cyano-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) vinyl] phosphoric acid diethyl ester
[2-[(2- (2-t-butoxycarbonylamino) ethoxy) -4-cyano-phenyl] vinyl] phosphoric acid diethyl ester compound 0.57 g (1.34 mmol) in dioxane 10 ml, 4N hydrogen chloride dioxane solution It was dissolved in 10 ml and stirred at room temperature for 1.5 hours. The crude product obtained by distilling off the solvent was dissolved in 20 ml of N, N-dimethylformamide (dehydrated), and 0.32 g (1.47 mmol) of pyrrolidylcarbamoylbenzoic acid, 2-chloro-1,3-dimethylimidazo 0.32 g (1.74 mmol) of nium chloride and 1.2 ml (8.04 mmol) of triethylamine were added and stirred overnight, and the solvent was distilled off. The obtained crude product was treated in the same manner as in step 11 of Example 1 to obtain the title compound.
Yield 0.52 g (0.99 mmol) Yield 74%
MS (ESI, m / z) 526 (MH +)
H-NMR (CDCl3) δ 1.34 (6H, t), 1.80-2.05 (4H, m), 3.40 (2H, t), 3.60 (2H, t), 3.95 (2H, br), 4.13 (4H, q), 4.25 (2H, t), 6.40 (2H, m), 7.17 (1H, s), 7.54 (2H, d) , 7.63 (1H, d), 7.85 (2H, d), 8.20 (1H, d).
Step 2 [2- (4-Amidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid diethyl ester Synthesis of monotrifluoroacetate
0.5 g (0.95 mmol) of [2- (4-cyano-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) vinyl] phosphoric acid diethyl ester obtained in Step 1 was used. It melt | dissolved in 10 ml of 4N hydrogen chloride dioxane solutions, 1 ml of ethanol was added, and it stirred at room temperature overnight. The residue obtained by distilling off the solvent was dissolved in 5 ml of ethanol, 0.3 g (4.76 mmol) of ammonium carbonate was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the resulting crude product was dissolved in 5 ml of ethanol, 0.1 g of 10% palladium-carbon was added, and the mixture was stirred overnight at room temperature in the presence of hydrogen. The crude product obtained by filtering through Celite and distilling off the solvent was subjected to the same operation as in Step 11 of Example 1 to obtain the title compound.
Yield 306 mg (0.46 mmol) Yield 49%
MS (ESI, m / z) 545 (MH +)
H-NMR (DMSO-d6) δ 1.16 (6H, t), 1.75-2.10 (6H, m), 2.83 (2H, br), 3.35 (2H, t), 3 .45 (2H, t), 3.70-4.00 (6H, m), 4.30 (2H, br), 7.42 (2H, m), 7.58 (3H, m), 7. 90 (2H, d), 8.86 (1H, br), 9.02 (2H, br), 9.25 (2H, br).
Step 3 [2- (4-Amidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphoric monoethyl ester Synthesis of monotrifluoroacetate
Synthesis of [2- (4-amidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphate monotrifluoroacetate
Compound [2- (4-amidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid diethyl ester monotrifluoroacetate 268 mg (0 .41 mmol) was dissolved in 3 ml of concentrated hydrochloric acid and stirred at 80 ° C. for 8 hours. The title compound was obtained by evaporating the solvent and conducting the same procedure as in Step 11 of Example 1.
[2- (4-Amidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid monoethyl ester monotrifluoroacetate
Yield 14.07 mg (0.022 mmol) Yield 5%
MS (ESI, m / z) 517 (MH +)
H-NMR (DMSO-d6) δ 1.16 (3H, t), 1.78-2.00 (6H, m), 2.85 (2H, br), 3.34 (2H, br), 3 .47 (2H, br), 3.72 (2H, br), 3.90 (2H, m), 4.30 (2H, br), 7.41 (3H, m), 7.58 (2H, d), 7.91 (2H, d), 8.90 (1H, br), 9.01 (2H, br), 9.22 (2H, br).
[2- (4-Amidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid monotrifluoroacetate
Yield 7.8 mg (0.013 mmol) Yield 3%
MS (ESI, m / z) 489 (MH +)
H-NMR (DMSO-d6) δ 1.75-1.92 (6H, m), 2.85 (2H, br), 3.35 (2H, br), 3.50 (2H, br), 3 .70 (2H, br), 4.25 (2H, br), 7.40 (3H, m), 7.59 (2H, d), 7.91 (2H, d), 8.94 (1H, br), 9.00 (2H, br), 9.23 (2H, br).
Example 4 (4S) -5- (5-amidino-2- (2- (diethoxyphosphate) ethyl) phenoxy) -4-((1- (1-pyridin-4-yl) piperidine-4-carbonyl) amino ) Pentanoic acid ditrifluoroacetate
Step 1 Synthesis of benzyl (4S) -4-((t-butoxycarbonyl) amino) -5-hydroxypentanoic acid
To a solution of 25 g (74.1 mmol) of t-butoxycarbonyl-D-glutamic acid-γ-benzyl ester in 350 ml of tetrahydrofuran was added 7.1 ml (74.1 mmol) of ethyl chloroformate and 10.3 ml (74.1 mmol) of triethylamine. Added at ° C. After stirring for 20 minutes, the produced triethylamine hydrochloride was filtered off, 5 g of ice and 2.8 g (74.1 mmol) of sodium borohydride were added at 0 ° C., stirred for 1 hour at room temperature, and 100 ml of 1N hydrogen chloride was added. Stir for 1 hour. The residue obtained by distilling off the solvent was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 11.25 g (34.8 mmol) Yield 47%
H-NMR (CDCl3) δ 1.43 (9H, s), 2.50 (2H, br), 3.50-3.70 (4H, m), 4.80 (1H, br), 5.10 (2H, s), 7.35 (5H, s).
Step 2 Synthesis of benzyl (4S) -4-((t-butoxycarbonyl) amino) -5- (3-ethenylphenoxy) pentanoic acid
11.25 g (34.8 mmol) of benzyl (4S) -4-((t-butoxycarbonyl) amino) -5-hydroxypentanoic acid obtained in Step 1 was dissolved in 120 ml of dichloromethane, and 9.7 ml (69. 6 mmol) was added, and at 0 ° C., 6.0 ml (52.2 mmol) of mesyl chloride was added and stirred at room temperature for 4 hours. The solvent was distilled off and ethyl acetate was used as an extraction solvent, followed by a conventional method to obtain a crude product. The obtained crude product was dissolved in 100 ml of N, N-dimethylformamide (dehydrated), 7.4 g (174 mmol) of lithium chloride was added, and the mixture was stirred at 50 ° C. for 6 hours. The solvent was distilled off and ethyl acetate was used as an extraction solvent, followed by a conventional method to obtain a crude product. The obtained crude product was dissolved in 150 ml of N, N-dimethylformamide (dehydrated) to give 6.8 g (27.7 mmol) of 3-hydroxy-4-iodobenzonitrile, 5.73 g (41.5 mmol) of potassium carbonate, and so on. 4.6 g (27.7 mmol) of potassium halide was added and stirred at 90 ° C. overnight. The solvent was distilled off, and the residue was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 6.64 g (13.5 mmol) Yield 39%
H-NMR (CDCl3) δ 1.44 (9H, s), 2.50 (2H, br), 3.60 (2H, br), 3.93 (2H, br), 4.90 (1H, br) ), 5.10 (2H, s), 6.94-7.04 (2H, m), 7.36 (5H, s), 7.88 (1H, d).
Step 3 of benzyl (4S) -4-((t-butoxycarbonyl) amino) -5- (2-((E) -2- (diethoxyphosphoryl) ethenyl) -5-ethenylphenoxy) pentanoic acid Composition
Benzyl (4S) -4-((t-butoxycarbonyl) amino) -5- (3-ethenylphenoxy) pentanoic acid 2.2 g (4.47 mmol) obtained in Step 2 was added to N, N-dimethylformamide ( Dehydrated) Dissolve in 20 ml, add 0.82 ml (5.36 mmol) of diethyl vinyl phosphonate, 11 mg (0.05 mmol) of palladium acetate, and 30 mg (0.09 mmol) of tris (2-methylphenyl) phosphine. Stir overnight. The solvent was distilled off, ethyl acetate was used as an extraction solvent, and the mixture was treated according to a conventional method, and purified by silica gel chromatography to obtain the title compound.
Yield 1.66 g (2.82 mmol) Yield 63%
H-NMR (CDCl3) δ 1.33 (6H, m), 1.43 (9H, s), 2.40-2.60 (2H, m), 3.85-4.20 (8H, m) , 5.00 (1H, br), 5.13 (2H, s), 6.00-6.50 (2H, m), 7.10-7.80 (8H, m).
Step 4 (4S) -5- (5-Amidino-2- (2- (diethoxyphosphate) ethyl) phenoxy) -4-((1- (1-pyridin-4-yl) piperidine-4-carbonyl) amino) Pentanoic acid Synthesis of ditrifluoroacetate
(4S) -5- (5-Amidino-2- (2- (ethoxy (hydroxy) phosphate) ethyl) phenoxy) -4-((1- (1-pyridin-4-yl) piperidine-4-carbonyl) Amino) pentanoic acid Synthesis of ditrifluoroacetate
Benzyl (4S) -4-((t-butoxycarbonyl) amino) -5- (2-((E) -2- (diethoxyphosphoryl) ethenyl) -5-ethenylphenoxy obtained in Step 3 ) 0.414 g (0.71 mmol) of pentanoic acid was dissolved in 3 ml of dioxane and 3 ml of 4N hydrogen chloride dioxane solution and stirred at room temperature for 2 hours. The solvent was distilled off, and the resulting crude product was dissolved in 5 ml of N, N-dimethylformamide (dehydrated) to give 0.16 g (0.78 mmol) of (1-pyridin-4-yl) piperidine-4-carboxylic acid, 2 -Chloro-1,3-dimethylimidazolium chloride 0.15 g (0.92 mmol) and triethylamine 0.6 ml (4.2 mmol) were added, and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the resulting crude product was subjected to the same operation as in Step 11 of Example 1. The obtained compound was dissolved in 2.6 ml of 4N hydrogen chloride dioxane solution, 0.26 ml of ethanol was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the resulting crude product was dissolved in 5 ml of ethanol, 0.2 g (3.53 mmol) of ammonium carbonate was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the resulting crude product was dissolved in 5 ml of ethanol, 0.2 g of 10% palladium-carbon was added, and the mixture was stirred overnight at room temperature in the presence of hydrogen. The mixture was filtered through Celite, the solvent was distilled off, and the resulting crude product was dissolved in 5 ml of concentrated hydrochloric acid and stirred at 80 ° C. for 1.5 hours. The title compound was obtained by evaporating the solvent and subjecting the resulting crude product to the same procedure as in Step 11 of Example 1.
(4S) -5- (5-Amidino-2- (2- (diethoxyphosphate) ethyl) phenoxy) -4-((1- (1-pyridin-4-yl) piperidine-4-carbonyl) amino) pentanoic acid Ditrifluoroacetate
Yield 26.7 mg (0.032 mmol) Yield 4.5%
H-NMR (DMSO-d6) δ 1.23 (6H, br), 1.50-2.10 (6H, m), 2.30 (2H, br), 2.55-3.15 (6H, m), 3.15-4.30 (12H, m), 7.20 (2H, br), 7.37-7.57 (2H, m), 8.10 (1H, br), 8.20. (2H, br), 9.10 (2H, br), 9.20 (2H, br), 9.40 (1H, br).
(4S) -5- (5-Amidino-2- (2- (ethoxy (hydroxy) phosphate) ethyl) phenoxy) -4-((1- (1-pyridin-4-yl) piperidine-4-carbonyl) Amino) pentanoic acid ditrifluoroacetate
Yield 25.5 g (0.032 mmol) Yield 4.5%
H-NMR (DMSO-d6) δ 1.19 (3H, t), 1.60 (2H, br), 1.80-2.00 (4H, m), 2.30 (2H, br), 2 58-2.95 (4H, m), 3.00-4.30 (10H, m), 7.18 (2H, d), 7.38 (2H, m), 8.06 (1H, d) ), 8.20 (2H, d), 9.04 (2H, br), 9.23 (3H, br).
Step 5 (4S) -5- (5-Amidino-2- (2-ethyl phosphate) phenoxy) -4-((1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino) pentanoic acid Ditrifluoroacetate
(4S) -5- (5-Amidino-2- (2- (ethoxy (hydroxy) phosphate) ethyl) phenoxy) -4-((1- (1-pyridin-4-yl)) obtained in Step 4 Piperidine-4-carbonyl) amino) pentanoic acid 23 mg (0.029 mmol) of ditrifluoroacetate was dissolved in 5 ml of dioxane, 0.03 ml (0.23 mmol) of trimethylsilyl bromide was added, and the mixture was stirred at room temperature for 3 days. The title compound was obtained by evaporating the solvent and subjecting the resulting crude product to the same procedure as in Step 11 of Example 1.
Yield 10 mg (0.013 mmol) Yield 44%
MS (ESI, m / z) 548 (MH +)
H-NMR (DMSO-d6) δ 1.60 (2H, br), 1.70-2.00 (4H, m), 2.30 (2H, br), 2.70 (2H, br), 2 .90 (2H, br), 3.20 (2H, br), 3.40-4.30 (6H, m), 7.17 (2H, d), 7.37 (2H, m), 8. 16 (1H, d), 8.20 (2H, d), 9.19 (2H, br), 9.25 (2H, br).
Example 5 [2- (4-Hydroxylamidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphoric acid ditrifluoroacetic acid salt
Step 1 [2- (4-Cyano-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) vinyl] phosphoric acid diethyl ester ditrifluoroacetic acid Salt synthesis
Dissolve 1 g (2.36 mmol) of [2-[(2- (2-t-butoxycarbonylamino) ethoxy) -4-cyano-phenyl] vinyl] phosphoric acid diethyl ester in 15 ml of dioxane and 15 ml of 4N hydrogen chloride dioxane solution. And stirred at room temperature for 2 hours. The crude product obtained by distilling off the solvent was dissolved in 30 ml of N, N-dimethylformamide (dehydrated), and 540 mg (2.60 mmol) of 1- (4-pyridyl) -4-piperidinecarboxylic acid hydrochloride, 2- Chloro-1,3-dimethylimidazolium chloride (520 mg, 3.07 mmol) and triethylamine (2 ml, 14.2 mmol) were added and stirred overnight. The title compound was obtained by evaporating the solvent and conducting the same procedure as in Step 11 of Example 1.
Yield 1.20 g (1.91 mmol) Yield 81%
MS (ESI, m / z) 513 (MH +)
H-NMR (DMSO-d6) δ 1.25 (6H, t), 1.60 (2H, br), 1.90 (2H, br), 2.60 (2H, br), 3.20 (2H) , Br), 3.50 (2H, br), 4.00 (4H, q), 4.20 (3H, br), 6.75 (1H, t), 7.19 (2H, d), 7 .46 (1H, d), 7.53-7.68 (2H, m), 7.92 (1H, d), 8.15 (1H, br), 8.21 (2H, d).
Step 2 [2- (4-Cyano-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphoric acid diethyl ester monotrifluoroacetic acid Salt synthesis
[2- (4-Cyano-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) vinyl] phosphoric acid diethyl ester obtained in Step 1 1.2 g (1.91 mmol) of monotrifluoroacetate was dissolved in 10 ml of ethanol, 0.12 g of 10% palladium-carbon was added, and the mixture was stirred overnight at room temperature in the presence of hydrogen. The crude product obtained by filtering through Celite and distilling off the solvent was subjected to the same operation as in Step 11 of Example 1 to obtain the title compound.
Yield 259 mg (0.41 mmol) Yield 22%
MS (ESI, m / z) 515 (MH +)
Step 3 [2- (4-Hydroxylamidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphate monoethyl ester Synthesis of fluoroacetates
Synthesis of [2- (4-hydroxylamidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphate ditrifluoroacetate
[2- (4-Cyano-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphoric acid diethyl ester obtained in Step 2 129 mg (0.206 mmol) of monotrifluoroacetate was dissolved in 5 ml of ethanol, 22 mg (0.31 mmol) of hydroxylamine hydrochloride and 0.05 ml (0.31 mmol) of triethylamine were added, and the mixture was stirred at 80 ° C. for 4 hours. The crude product obtained by distilling off the solvent was added with 5 ml of concentrated hydrochloric acid and stirred at 80 ° C. for 4 hours. The title compound was obtained by evaporating the solvent and conducting the same procedure as in Step 11 of Example 1.
[2- (4-Hydroxylamidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphoric acid monoethyl ester ditrifluoroacetic acid salt
Yield 31.4 mg (0.042 mmol) Yield 20%
MS (ESI, m / z) 520 (MH +)
H-NMR (DMSO-d6) δ 1.20 (3H, t), 1.50-1.70 (2H, m), 1.80-2.00 (4H, m), 2.55-2. 70 (2H, m), 2.75-2.90 (2H, m), 3.20 (2H, br), 3.50 (2H, br), 3.95 (2H, q), 4.10 (2H, br), 4.20 (1H, br), 7.17-7.26 (3H, m), 7.39 (2H, d), 8.20-8.30 (4H, m).
[2- (4-Hydroxylamidino-2- [2-[(1- (1-pyridin-4-yl) piperidin-4-carbonyl) amino] ethoxy] phenyl) ethyl] phosphate ditrifluoroacetate
Yield 4.9 mg (0.007 mmol) Yield 3%
MS (ESI, m / z) 492 (MH +)
H-NMR (DMSO-d6) δ 1.58 (2H, br), 1.80-1.83 (4H, m), 2.63 (2H, br), 2.80 (2H, br), 3 10-4.00 (4H, m), 4.05 (2H, br), 4.15 (1H, br), 7.15-7.23 (3H, m), 7.32 (2H, d) ), 8.19 (2H, d), 8.29 (2H, br).
Example 6 [2- (4-Hydroxylamidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid monotrifluoroacetate
Step 1 [2- (4-Cyano-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid diethyl ester Synthesis of monotrifluoroacetate
[2- (4-Cyano-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) vinyl] phosphoric acid diethyl ester 0 obtained by the same procedure as in Step 1 of Example 3. .88 g (1.67 mmol) was dissolved in 10 ml of ethanol, 0.1 g of 10% palladium-carbon was added, and the mixture was stirred overnight at room temperature in the presence of hydrogen. The crude product obtained by filtering through Celite and distilling off the solvent was subjected to the same operation as in Step 11 of Example 1 to obtain the title compound.
Yield 692 mg (1.31 mmol) Yield 78%
MS (ESI, m / z) 528 (MH +)
Step 2 [2- (4-Hydroxylamidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) vinyl] phosphate monoethyl ester Synthesis of monotrifluoroacetate
Synthesis of [2- (4-hydroxylamidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) vinyl] phosphate monotrifluoroacetate
[2- (4-Cyano-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) ethyl] phosphoric acid diethyl ester obtained in Step 1 0.34 g of monotrifluoroacetic acid salt ( 0.66 mmol) was dissolved in 10 ml of ethanol, 70 mg (0.98 mmol) of hydroxylamine hydrochloride and 0.14 ml (0.98 mmol) of triethylamine were added, and the mixture was stirred at 80 ° C. for 5 hours. The crude product obtained by distilling off the solvent was added with 5 ml of concentrated hydrochloric acid and stirred at 80 ° C. for 2.5 hours. The title compound was obtained by evaporating the solvent and conducting the same procedure as in Step 11 of Example 1.
[2- (4-hydroxylamidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) vinyl] phosphoric acid monoethyl ester monotrifluoroacetate
Yield 103.5 mg (0.16 mmol) Yield 24%
MS (ESI, m / z) 533 (MH +)
H-NMR (DMSO-d6) δ 1.16 (3H, t), 1.75-2.00 (6H, m), 2.85 (2H, br), 3.35 (2H, t), 3 .50 (2H, t), 3.70 (2H, br), 3.88 (2H, q), 4.25 (2H, br), 7.25 (1H, d), 7.30 (1H, s), 7.39 (1H, d), 7.58 (2H, d), 7.91 (2H, d), 8.90 (2H, br).
[2- (4-hydroxylamidino-2- [2- [4- (1-pyrrolidinecarbamoyl) benzoylamino] ethoxy] phenyl) vinyl] phosphate monotrifluoroacetate
Yield 46.32 mg (0.075 mmol) Yield 11%
MS (ESI, m / z) 505 (MH +)
H-NMR (DMSO-d6) δ 1.75-2.00 (6H, m), 2.88 (2H, br), 3.35 (2H, t), 3.50 (2H, t), 3 .75 (2H, br), 4.25 (2H, br), 7.24 (1H, d), 7.31 (1H, s), 7.37 (1H, d), 7.91-8. 00 (2H, m), 8.96 (2H, m).
Example 7 Measurement of activated blood coagulation factor factor X inhibitory activity
130 μl of a 100 mM Tris-HCl buffer adjusted to pH 8.4 is added to 10 μl of an aqueous solution of the evaluation compound, and then human activated blood coagulation factor factor X (manufactured by Enzyme Research) is added to the pH 8.4 Tris-HCl buffer with a pH of 0.8. 10 μl of a solution adjusted to 5 units / ml was added and incubated at room temperature for 10 minutes. Next, a solution in which N-benzoyl-L-isoleucine-glutamine-glycine-L-arginine-P-nitroanilide hydrochloride (manufactured by Peptide Institute, Inc.) was adjusted to 0.8 mM with pH 8.4 Tris-HCl buffer. 50 μl was added, the absorbance was measured, and the initial reaction rate was determined. A control prepared by adding 10 μl of Tris-HCl buffer adjusted to pH 8.4 instead of the evaluation compound was used as a control. Absorbance was measured using MICROPLATE READER Model 3550-UV (BIO RAD) at a wavelength of 405 nm for 16 minutes at 15 second intervals. A negative logarithmic value of the concentration of the evaluation compound when 50% of the activity (initial rate) of the active blood coagulation factor X when no evaluation compound is added is determined (abbreviated as pIC50), and activated blood coagulation factor X It was used as an index of inhibitory activity.
Table 1 shows the activated blood coagulation factor X inhibitory activity of typical compounds.
Example 8 Measurement of inhibitory activity of thrombin
130 μl of 100 mM Tris-HCl buffer adjusted to pH 8.4 is added to 10 μl of an aqueous solution of the evaluation compound, and then 10 μl of human thrombin (manufactured by SIGMA) adjusted to 2 units / ml with pH 8.4 Tris-HCl buffer. And incubated for 10 minutes at room temperature. Next, 50 μl of a solution prepared by adjusting D-phenylalanine-L-pipecolyl-L-arginine-P-nitroanilide dihydrochloride (Daiichi Kagaku, S-2238) to 0.4 mM with pH 8.4 Tris-HCl buffer In addition, the absorbance was measured to determine the initial reaction rate. A control was prepared by adding 10 μl of Tris-HCl buffer adjusted to pH 8.4 instead of the solution of the evaluation compound. Absorbance was measured using MICROPLATE READER Model 3550-UV (BIO RAD) at a wavelength of 405 nm for 16 minutes at 15 second intervals. A negative logarithmic value of the concentration of the evaluation compound when 50% of the thrombin activity (initial rate) when the evaluation compound was not added was inhibited (abbreviated as pIC50) was used as an index of thrombin inhibition activity.
Table 1 below shows the thrombin inhibitory activity of representative compounds.
Example 9 Measurement of anticoagulant activity
Anticoagulant activity was determined using a prothrombin time (PT) assay. PT measurement was performed as shown below. That is, blood was collected from a healthy person, and 1/10 volume of 3.8% trisodium citrate aqueous solution was added, and plasma was separated by centrifugation. To 45 μl of plasma, 5 μl of DMSO solution containing the evaluation compound was added and incubated at room temperature for 2 minutes. The test tube containing the plasma solution was placed in a Sysmex CA-3000 fully automatic blood coagulation measurement apparatus (Toa Medical Electronics Co., Ltd.) and then incubated at 37 ° C. for 3 minutes. Sysmex PT II (Toa Medical Electronics Co., Ltd., rabbit brain tissue thromboplastin, 13.2 mM calcium chloride) 100 μl was added. PT was automatically measured by the same apparatus. A control added with 5 μl of DMSO instead of the solution of the evaluation compound was used as a control, and a negative logarithmic value of the evaluation compound concentration that doubles the PT of the control was obtained (abbreviated as pPT2), and used as an index of anticoagulant activity.

In addition, the compound described in Example 1 (compound represented by formula (2-1)) also showed excellent anticoagulant activity (pPT2 = 6.8).
From this result, it was found that the benzamidine derivative of the present invention showed a high inhibitory activity specific to activated blood coagulation factor factor X and a high anticoagulant activity based on this. The structural formulas of the compounds of the present invention described in the examples are shown below.

An anticoagulant comprising the compound of the present invention or a salt thereof as an active ingredient exhibits an excellent anticoagulant action based on an activated blood coagulation factor X inhibitory action. Therefore, the compound of the present invention is useful for diseases in cerebrovascular disorders such as cerebral infarction, stroke, cerebral thrombus, cerebral embolism, transient cerebral ischemic attack (TIA), subarachnoid hemorrhage (vasospasm), acute and chronic myocardial infarction, Stable angina, diseases in ischemic heart diseases such as coronary thrombus, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation syndrome, and artificial blood vessels Blood flow such as thrombus formation after surgery and prosthetic valve replacement, reocclusion and restenosis after coronary artery bypass surgery, percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary artery recanalization (PTCR) It can be used as a prophylactic / therapeutic agent for reocclusion and restenosis after reconstruction, and thrombus formation during extracorporeal circulation.

Claims (13)

A benzamidine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.

[Wherein, X is a hydrogen atom, a carboxyl group, an alkoxycarbonyl group having 2 to 4 carbon atoms, an optionally substituted alkyl group having 1 to 3 carbon atoms, or an optionally substituted benzyl group. Where the substituent in the case of having a substituent represents either a carboxyl group or an alkoxycarbonyl group having 2 to 8 carbon atoms,
V represents either a benzoyl group or a piperidinecarbonyl group which may have a substituent, and in the case of having a substituent, the substituent is an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, or 6 to 6 carbon atoms. It represents any of 10 aryl groups, heteroaryl groups having 4 to 5 carbon atoms, carbamoyl groups, and mono- or dialkylcarbamoyl groups having 2 to 7 carbon atoms. ] In the formula, V represents either a benzoyl group or a piperidinecarbonyl group which may have a substituent, where the substituent in the case of having a substituent is an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, carbon The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 5 carbon atoms. 2. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is a group represented by any of a hydrogen atom, a carboxymethyl group or a carboxyethyl group. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein X is a group represented by any one of a hydrogen atom, a carboxymethyl group and a carboxyethyl group. In the formula, V is represented by any of 1-acetimidoyl-4-piperidyloxybenzoyl group, 1- (4-pyridyl) -piperidine-4-carbonyl group or 4- (1-pyrrolidinecarbonyl) benzoyl group. The benzamidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof. The benzamidine derivative according to claim 2, wherein V is any one of 1-acetimidoyl-4-piperidyloxybenzoyl group and 1- (4-pyridyl) -piperidine-4-carbonyl group, or a pharmaceutical product thereof Acceptable salt. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 2, represented by the following formula (2-1).

The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, represented by the following formulas (2-2) to (2-4).

The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, represented by the following formulas (2-5) to (2-6):

A pharmaceutical composition comprising the benzamidine derivative according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient. An anticoagulant or a prophylactic / therapeutic agent for thrombosis or embolism containing the benzamidine derivative according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient. 10. A disease in cerebrovascular disorder, a disease in ischemic heart disease, a disease in pulmonary vascular disorder, peripheral, comprising as an active ingredient the benzamidine derivative according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof. Arterial occlusion, deep vein thrombosis, generalized intravascular coagulation syndrome, thrombus formation after artificial vascular surgery and valve replacement, reocclusion and restenosis after coronary artery bypass surgery, reocclusion and restenosis after revascularization, A prophylactic / therapeutic agent for thrombus formation during extracorporeal circulation. A prophylactic / therapeutic agent for cerebral infarction or stroke comprising the benzamidine derivative according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient.